Update on -Borne Rickettsioses around the World: a Geographic Approach

Philippe Parola,a Christopher D. Paddock,b Cristina Socolovschi,a Marcelo B. Labruna,c Oleg Mediannikov,a Tahar Kernif,d Mohammad Yazid Abdad,e* John Stenos,e Idir Bitam,f Pierre-Edouard Fournier,a Didier Raoulta Aix Marseille Université, Unité de Recherche en Maladies Infectieuses et Tropicales Emergentes (URMITE), UM63, CNRS 7278, IRD 198, Inserm 1095, WHO Collaborative Center for Rickettsioses and Other -Borne Bacterial Diseases, Faculté de Médecine, Marseille, Francea; Centers for Disease Control and Prevention, Atlanta, Georgia, USAb; Departamento de Medicina Veterinária Preventiva e Saúde , Faculdade de Medicina Veterinária e Zootecnia Universidade de São Paulo, Cidade Universitária, São Paulo, SP, Brazilc; Service d’Ecologie des Systèmes Vectoriels, Institut Pasteur d’Algérie, Algiers, Algeriad; Division of Veterinary and Biomedical Science, Murdoch University, Australian Rickettsial Reference Laboratory, Barwon Health, Geelong, Victoria, Australiae; University of Boumerdes, Boumerdes, Algeriaf

SUMMARY ...... 658 INTRODUCTION ...... 659 TAXONOMIC AND GENOMIC BACTERIOLOGY: THE REVOLUTION ...... 659 RELATIONSHIP BETWEEN SPOTTED FEVER GROUP RICKETTSIAE, IXODID , AND VERTEBRATE HOSTS ...... 667 TICK-BORNE RICKETTSIAE IN THE AMERICAS ...... 668 North and Central America ...... 668 Species identified as pathogens ...... 668 (i) rickettsii ...... 668 (ii) ...... 670 (iii) Rickettsia massiliae ...... 670 (iv) ...... 670 (v) Rickettsia philipii (Rickettsia 364D) ...... 671 Species of unknown pathogenicity...... 671 (i) Rickettsia bellii...... 671 (ii) Rickettsia canadensis ...... 671 (iii) Rickettsia montanensis ...... 671 (iv) Rickettsia peacockii...... 671 (v) Rickettsia rhipicephali...... 671 Nonvalidated, incompletely described, or uncultivated species...... 671 South America ...... 672 Species identified as pathogens ...... 672 (i) ...... 672 (ii) Rickettsia parkeri ...... 673 (iii) Rickettsia massiliae ...... 673 (iv) Rickettsia sp. strain Atlantic rainforest or strain Bahia ...... 674 Species of unknown pathogenicity...... 674 (i) Rickettsia rhipicephali ...... 674 (ii) Rickettsia bellii ...... 674 (iii) Rickettsia monteiroi ...... 674 Nonvalidated, incompletely described, or uncultivated species...... 674 TICK-BORNE RICKETTSIAE IN EUROPE ...... 674 Species Identified as Pathogens ...... 674 subsp. conorii...... 674 Rickettsia conorii subsp. israelensis ...... 676 Rickettsia conorii subsp. caspia ...... 676 Rickettsia conorii subsp. indica ...... 676 Rickettsia massiliae ...... 676 subsp. mongolitimonae ...... 677 Rickettsia slovaca and Rickettsia raoultii ...... 677 Rickettsia monacensis ...... 677 Rickettsia aeschlimannii ...... 677 Rickettsia helvetica...... 678 Rickettsia sibirica subsp. sibirica...... 678 (continued)

Address correspondence to Philippe Parola, [email protected]. * Present address: Mohammad Yazid Abdad, Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea. Copyright © 2013, American Society for Microbiology. All Rights Reserved. doi:10.1128/CMR.00032-13

October 2013 Volume 26 Number 4 Clinical Microbiology Reviews p. 657–702 cmr.asm.org 657 Parola et al.

Species of Unknown Pathogenicity ...... 678 Nonvalidated, Incompletely Described, or Uncultivated Species...... 678 TICK-BORNE RICKETTSIAE IN AFRICA ...... 679 North Africa...... 679 Species identified as pathogens ...... 679 (i) Rickettsia conorii subsp. conorii ...... 679 (ii) Rickettsia conorii subsp. israelensis...... 679 (iii) Rickettsia aeschlimannii ...... 679 (iv) Rickettsia sibirica subsp. mongolitimonae ...... 679 (v) Rickettsia slovaca and Rickettsia raoultii...... 679 (vi) Rickettsia monacensis ...... 679 (vii) Rickettsia massiliae ...... 680 (viii) Rickettsia africae ...... 680 (ix) Rickettsia helvetica ...... 680 Nonvalidated, incompletely described, or uncultivated species...... 680 Sub-Saharan Africa ...... 680 Species identified as pathogens ...... 680 (i) Rickettsia africae ...... 680 (ii) Rickettsia conorii subsp. conorii...... 681 (iii) Rickettsia conorii subsp. caspia...... 681 (iv) Rickettsia aeschlimannii ...... 681 (v) Rickettsia sibirica subsp. mongolitimonae ...... 681 (vi) Rickettsia massiliae...... 682 Species of unknown pathogenicity...... 682 Nonvalidated, incompletely described, or uncultivated species...... 682 TICK-BORNE RICKETTSIAE IN ASIA ...... 682 Species Identified as Pathogens ...... 682 Rickettsia sibirica subsp. sibirica ...... 682 Rickettsia heilongjiangensis ...... 682 ...... 682 Rickettsia sibirica subsp. mongolitimonae ...... 683 Rickettsia conorii subsp. conorii...... 683 Rickettsia conorii subsp. indica ...... 683 Rickettsia conorii subsp. israelensis ...... 683 ...... 683 Rickettsia tamurae...... 683 “Candidatus Rickettsia kellyi” ...... 684 Rickettsia aeschlimannii ...... 684 Rickettsia raoultii ...... 684 Rickettsia slovaca ...... 684 Rickettsia helvetica...... 684 Rickettsia massiliae ...... 684 Rickettsia monacensis ...... 684 Rickettsia africae...... 684 Species of Unknown Pathogenicity ...... 684 Nonvalidated, Incompletely Described, or Uncultivated Species...... 684 TICK-BORNE RICKETTSIAE IN AUSTRALIA AND THE PACIFIC ...... 684 Species Identified as Pathogens ...... 684 ...... 684 Rickettsia honei...... 685 Rickettsia honei strain marmionii ...... 685 Rickettsia africae...... 685 Species of Unknown Pathogenicity ...... 686 Rickettsia gravesii ...... 686 Rickettsia argasii...... 686 Nonvalidated, Incompletely Described, or Uncultivated Species...... 686 NEW APPROACHES TO DIAGNOSIS ...... 686 NEW TOOLS TO IDENTIFY TICKS ...... 687 TREATMENT PERSPECTIVE ...... 687 CONCLUSION...... 688 ACKNOWLEDGMENTS...... 688 REFERENCES ...... 688 AUTHOR BIOS ...... 700

SUMMARY eases. However, in the past 25 years, the scope and importance of Tick-borne rickettsioses are caused by obligate intracellular bac- the recognized tick-associated rickettsial pathogens have in- teria belonging to the spotted fever group of the genus Rickettsia. creased dramatically, making this complex of diseases an ideal These zoonoses are among the oldest known vector-borne dis- paradigm for the understanding of emerging and reemerging in-

658 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World fections. Several species of tick-borne rickettsiae that were consid- results of their multifaceted work. Many original articles were ered nonpathogenic for decades are now associated with human published after these meetings. infections, and novel Rickettsia species of undetermined pathoge- The time has come to summarize current knowledge on tick- nicity continue to be detected in or isolated from ticks around the borne rickettsioses in a comprehensive review, using a geographic world. This remarkable expansion of information has been driven approach and the 2005 review as a background for historical, ep- largely by the use of molecular techniques that have facilitated the idemiological, and diagnostic information. Data for the present identification of novel and previously recognized rickettsiae in review were obtained from publications identified by PubMed ticks. New approaches, such as swabbing of eschars to obtain ma- searches from 2005 to 2012. Search terms were combinations of terial to be tested by PCR, have emerged in recent years and have the words “ticks,” “rickettsia,” “rickettsioses,” “spotted fever,” played a role in describing emerging tick-borne rickettsioses. and “.” A secondary manual search of the references cited Here, we present the current knowledge on tick-borne rickettsiae in these articles was also performed to find relevant articles that and rickettsioses using a geographic approach toward the epide- had been reviewed. Additionally, the same terms were searched in miology of these diseases. the GenBank database to identify additional rickettsiae or rickett- sial DNA samples that have been detected in ticks. INTRODUCTION embers of the genus Rickettsia (family ; order TAXONOMIC AND GENOMIC BACTERIOLOGY: THE MRickettsiales) may be classified into spotted fever group REVOLUTION (SFG) rickettsiae, typhus group rickettsiae, the Rickettsia bellii Currently, 26 Rickettsia species with validated and published group, and the Rickettsia canadensis group (1). Tick-borne rick- names have been reported (http://www.bacterio.cict.fr/qr ettsioses are caused by obligate intracellular belonging to /rickettsia.html), including Rickettsia asiatica (3), Rickettsia hei- the SFG of the genus Rickettsia (2). These zoonoses are among the longjiangensis (4), Rickettsia hoogstraalii (5), Rickettsia raoultii (6), oldest-known vector-borne diseases (2). However, the scope and and Rickettsia tamurae (7), which were reported since 2005 (2). In importance of the recognized tick-associated rickettsial pathogens addition to these 26 species, subspecies have been proposed within have increased dramatically in the past 25 years, making this com- the Rickettsia conorii (8) and Rickettsia sibirica (9) species. The plex of diseases an ideal paradigm to help understand emerging taxonomic criteria used to describe new Rickettsia species have not and reemerging infections. The last major review of tick-borne changed over the past 10 years (10). However, the sizes of the rickettsioses was published in 2005 (2). Since then, rickettsiology Rickettsia genomes are small, and their sequences are available for has undergone a significant transformation. Several species of most validated species. After proposals to include genomic data tick-borne rickettsiae that were considered nonpathogenic for de- among taxonomic criteria (11), it could be suggested that genome cades are now associated with human infections (Table 1), and sequences should be mandatory for the description of new Rick- novel Rickettsia species of undetermined pathogenicity (Table 2) ettsia species. Currently, genomes from 23 of the 26 validated continue to be detected in or isolated from ticks around the world. Rickettsia species are available, and for 11 of these species, the This remarkable expansion of information has been driven genomes from 2 to 8 isolates are available (Table 3). Compared to largely by the use of molecular techniques that have facilitated the the genomes of free-living bacteria, rickettsial genomes exhibit identification of novel and previously recognized rickettsiae in several unusual properties. These genomes are small, ranging ticks. Until relatively recently, the diagnosis of tick-borne SFG from 1.11 Mb for , the agent of the flea-borne mu- rickettsioses was confirmed almost exclusively by serologic meth- rine typhus, to 2.1 Mb for the “Rickettsia endosymbiont of ods. Even when using a microimmunofluorescence (MIF) assay, scapularis.” Their GϩC content is low, ranging from 29% (R. the current reference method, a positive serologic reaction does typhi) to 33% (Rickettsia endosymbiont of ). By not necessarily imply that the patient’s illness was caused by the studying the genome size and gene content of bacteria in relation rickettsial species used as the antigen in the assay due to antigenic to their lifestyle, Merhej et al. demonstrated that genome degra- cross-reactivity among SFG rickettsiae (2). The recognition of dation, especially gene loss, has been a driving force in the adap- multiple distinct tick-borne SFG rickettsioses during recent years tation of rickettsiae and other intracellular bacteria to live within has been greatly facilitated by the broad use of cell culture systems eukaryotic cells (12). By comparing the genome of Rickettsia afri- and molecular methods for identifying rickettsiae from human cae, a mildly pathogenic organism in humans, to those of the more samples, including the use of quantitative PCR (qPCR) (2). New pathogenic species R. conorii, Rickettsia rickettsii, and Rickettsia approaches, such as the use of swabs to obtain material from prowazekii, Fournier et al. hypothesized that genome degradation eschars to be tested by PCR, have recently emerged (2). Finally, in rickettsiae was associated with increasing virulence (13). This many well-characterized SFG Rickettsia species and recently or reductive evolution is marked by a notably large proportion of incompletely described rickettsiae that were previously consid- noncoding sequences resulting in degraded genes with functions ered to be restricted to a specific tick host or geographical location in biosynthetic pathways. However, rickettsial genomes also con- have recently been detected on different continents and in various tain a variety of duplicated or repeated genes or DNA fragments. tick hosts. In addition, some noncoding sequences are highly conserved, sug- In recent years, rickettsiologists, including clinicians, scien- gesting a potential function for these sequences (1). Among du- tists, veterinarians, field investigators, and laboratory profession- plicated or repeated genomic elements, rickettsial genomes con- als, have contributed to the accumulation of knowledge in this tain palindromic repeats, modules encoding type IV secretion rapidly progressing field. The 4th, 5th, and 6th International systems, tetratricopeptide and ankyrin repeat motifs that possibly Meetings on Rickettsiae and Rickettsial Diseases, organized in play a role in pathogenicity by mediating interactions with eukary- Spain (2005), France (2008), and Greece (2011), gathered approx- otic cells, toxin-antitoxin (TA) modules, and paralogous gene imately 300 experts who traveled from 5 continents to present the families (sca, spoT, tlc, proP, and ampG)(1). In addition, several

October 2013 Volume 26 Number 4 cmr.asm.org 659 Parola et al.

TABLE 1 Tick-borne spotted fever group rickettsial agents of human diseases Geographical Rickettsia species or strain Recognized or potential tick vector(s) Comment(s) (including related disease[s]) distributiona Rickettsia aeschlimannii variegatum, Rhipicephalus Spotted fever Sub-Saharan Africa annulatus, Rhipicephalus evertsi evertsi, Rhipicephalus appendiculatus, Hyalomma marginatum rufipes, Hyalomma truncatum Hyalomma marginatum marginatum, Spotted fever Europe Hyalomma anatolicum excavatum, , , Rhipicephalus turanicus, Rhipicephalus bursa Haemaphysalis punctata, Hyalomma No human cases; identified in ticks in Asia marginatum, Hyalomma detritum Kazakhstan and Israel Hyalomma detritum detritum, Hyalomma Detected in humans in Tunisia and Algeria North Africa marginatum marginatum, Hyalomma and in ticks in Algeria, Morocco, aegyptium, Hyalomma marginatum rufipes, Tunisia, and Egypt Hyalomma dromedari, Hyalomma truncatum

Rickettsia africae Amblyomma variegatum, Amblyomma Sub-Saharan Africa hebraeum, Amblyomma compressum, A. lepidum, Rhipicephalus annulatus, Rhipicephalus evertsi, Rhipicephalus decoloratus, Rhipicephalus sanguineus, Rhipicephalus geigyi, Hyalomma impeltatum Amblyomma variegatum Imported from Africa to the West Indies North and Central during the early 1800s; currently America established in Guadeloupe, St. Kitts, Nevis, Dominica, U.S. Virgin Islands, Montserrat, St. Lucia, Martinique, and Antigua; causes eschar-associated illness, with clinical cases reported from Guadeloupe Amblyomma loculosum African tick bite fever Pacific Islands Hyalomma aegyptium No human cases reported from Asia; Asia identified in ticks in Turkey Hyalomma dromedarii No human cases; detected in dromedary North Africa ticks in sub-Saharan Algeria and Egypt

Rickettsia australis , Ixodes tasmani, Ixodes Australia cornuatus

Rickettsia sp. strain Atlantic Amblyomma ovale, Amblyomma aureolatum, Genetically related to R. parkeri, R. africae, South America rainforest or Bahia Rhipicephalus sanguineus and R. sibirica; 2 nonfatal cases reported in Brazil; symptoms include rash, eschar, and lymphadenopathy

Rickettsia conorii subsp. caspia Rhipicephalus pumilio, Rhipicephalus sanguineus Astrakhan fever Europe Rhipicephalus sanguineus, Rhipicephalus pumilio Astrakhan fever Sub-Saharan Africa

Rickettsia conorii subsp. conorii Rhipicephalus sanguineus Mediterranean spotted fever Europe Rhipicephalus sanguineus Mediterranean spotted fever human cases North Africa reported and detected in brown ticks in all North Africa areas Rhipicephalus sanguineus, Rhipicephalus evertsi Mediterranean spotted fever Sub-Saharan Africa evertsi, Rhipicephalus simus, Rhipicephalus mushamae, Haemaphysalis punctaleachi, Haemaphysalis leachi Rhipicephalus sanguineus, Rhipicephalus bursa Asiatic part of Turkey Asia

Rickettsia conorii subsp. indica Rhipicephalus sanguineus Indian tick typhus Europe, Asia

R. conorii subsp. israelensis Rhipicephalus sanguineus Israeli tick typhus Europe, Asia Rhipicephalus sanguineus Israeli tick bite fever; 2 cases of ISF from North Africa Sfax confirmed by detection of rickettsia in skin biopsy specimens (Continued on following page)

660 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

TABLE 1 (Continued) Geographical Rickettsia species or strain Recognized or potential tick vector(s) Comment(s) (including related disease[s]) distributiona Rickettsia heilongjiangensis Haemaphysalis concinna, Haemaphysalis Far-Eastern spotted fever in Russia, China, Asia japonica douglasi, Haemaphysalis flava, South Korea, Japan silvarum

Rickettsia helvetica Serologically confirmed cases only in Laos Asia and Thailand; in Ixodes ticks in Japan and Turkey Ixodes ricinus Europe Ixodes ricinus No human cases; detected in Ixodes spp. in North Africa Algeria and Morocco

Rickettsia honei Bothriocroton hydrosauri Flinders Island spotted fever Asia, Australia, and Pacific Ixodes sp. Spotted fever identical to Flinders Island Asia spotted fever in Australia

Rickettsia honei strain Haemaphysalis novaeguineae Australian spotted fever Australia marmionii

Rickettsia japonica Haemaphysalis flava, Haemaphysalis hystricis, in Japan and South Asia Haemaphysalis longicornis, Haemaphysalis Korea cornigera, Haemaphysalis formosensis, I. ovatus, D. taiwanensis

“Candidatus Rickettsia kellyi” Unknown A single case reported from India; several Asia amplicons from patients are referenced in GenBank

Rickettsia massiliae Rhipicephalus sanguineus Recognized pathogen in other countries North and Central and detected in brown dog ticks in America Arizona and California; no confirmed human cases in the U.S. Rhipicephalus sanguineus 1 case reported in a patient in Spain, South America recently arrived from Argentina; also reported to infect R. sanguineus in Argentina Rhipicephalus turanicus, Rhipicephalus Spotted fever Europe sanguineus, Rhipicephalus bursa, Rhipicephalus pusillus, Ixodes ricinus Rhipicephalus evertsi, Haemaphysalis paraleachi, Spotted fever Sub-Saharan Africa Rhipicephalus senegalensis, Rhipicephalus guilhoni, Rhipicephalus lunulatus, Rhipicephalus sulcatus, Rhipicephalus muhsamae Rhipicephalus turanicus, Rhipicephalus Identified in ticks in Israel Asia sanguineus Rhipicephalus sanguineus, Rhipicephalus No human cases; detected in Rhipicephalus North Africa turanicus spp. in Morocco, Algeria, and Tunisia

R. monacensis Ixodes ricinus Spotted fever (first clinical description Europe 2007) Ixodes persulcatus Found only in ticks in Turkey Ixodes ricinus No human cases; identified in Ixodes spp. North Africa in Tunisia, Algeria, and Morocco Rickettsia parkeri Amblyomma maculatum, Amblyomma Southeastern U.S.; causes mild, eschar- North and Central americanum, associated ; despite the America occurrence of A. maculatum in Central America, no confirmed cases have been reported from that region (Continued on following page)

October 2013 Volume 26 Number 4 cmr.asm.org 661 Parola et al.

TABLE 1 (Continued) Geographical Rickettsia species or strain Recognized or potential tick vector(s) Comment(s) (including related disease[s]) distributiona Amblyomma triste, Amblyomma tigrinum Causes spotted fever in Uruguay and South America Argentina; symptoms include rash, eschar, and lymphadenopathy; no fatal cases reported; also reported to infect ticks in Brazil and Bolivia

Rickettsia philipii (364D) Dermacentor occidentalis California; causes a relatively mild, eschar- North and Central associated illness; only a few recognized America cases

Rickettsia raoultii Dermacentor marginatus, Dermacentor SENLAT (old TIBOLA/DEBONEL) Europe reticulatus, Ixodes ricinus Dermacentor silvarum, Dermacentor reticulatus, No human cases; identified in Asia Dermacentor marginatus, Dermacentor Dermacentor species ticks in North Asia nuttalli, Dermacentor niveus, Haemaphysalis and in Haemaphysalis and Amblyomma ornithophila, Haemaphysalis shimoga, ticks in South Asia Haemaphysalis lagrangei, Amblyomma testudinarium Dermacentor marginatus No human cases; identified in North Africa Dermacentor spp. in Morocco

Rickettsia rickettsii , Dermacentor variabilis, Causes Rocky Mountain spotted fever, the North and Central Dermacentor occidentalis, Dermacentor nitens, most severe rickettsiosis in the world; America Rhipicephalus sanguineus, Amblyomma occurs sporadically and infrequently in cajennense, ticks throughout Canada, the U.S., Amblyomma imitator, Haemaphysalis Mexico, Costa Rica, and Panama leporispalustris , Amblyomma Causes the most severe spotted fever, South America aureolatum, Rhipicephalus sanguineus namely, Rocky Mountain spotted fever or Brazilian spotted fever; reported in Argentina, Brazil, and Colombia; current case fatality rate of 20–40%

Rickettsia sibirica subsp. Hyalomma anatolicum excavatum, LAR Europe mongolitimonae Rhipicephalus pusillus Hyalomma truncatum LAR Sub-Saharan Africa Hyalomma asiaticum Type strain isolated in China; no cases Asia from Asia have been reported; identified in Israel Hyalomma sp. 1 human case North Africa

Rickettsia sibirica subsp. Dermacentor nuttalli, Dermacentor marginatus, Siberian tick typhus in Russia, China, and Asia sibirica Dermacentor reticulatus, Dermacentor Mongolia silvarum, Dermacentor sinicus, Haemaphysalis yeni, Haemaphysalis concinna, Ixodes persulcatus

Rickettsia slovaca Dermacentor marginatus, Dermacentor SENLAT (TIBOLA/DEBONEL) Europe reticulatus Dermacentor ticks No human cases in Asia; identified in Asia Russia and China Dermacentor marginatus SENELAT (TIBOLA DEBONEL); no North Africa human cases; detected in Dermacentor ticks from Algeria and Morocco

Rickettsia tamurae Amblyomma testudinarium Case was reported from Japan and Laos Asia a See figures. mobile genetic elements have been identified. These elements in- species (14). In addition, plasmids in rickettsiae can be polymor- clude plasmids in at least 10 species, although it was previously phic, as observed for , where a plasmid exists in both thought that rickettsiae lacked plasmids. One notable aspect of a 62-kb and a 39-kb form (15). The discovery of plasmids and Rickettsia plasmids is that there are multiple plasmids in several evidence for conjugation in these organisms suggest that lateral

662 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

TABLE 2 Tick-borne spotted fever group rickettsiae of unknown pathogenicity and nonvalidated, incompletely described, or uncultivated species isolated or detected in ticks Rickettsia species or strain Associated tick(s) Comment(s) Geographical distributiona Rickettsia aeschlimannii-like Amblyomma tigrinum Reported in Bolivia; very similar to Old Word South America R. aeschlimannii

Strain AL Amblyomma longirostre Reported in bird ticks in Brazil; could be R. South America amblyommii

“Candidatus Rickettsia amblyommii” Amblyomma americanum, Amblyomma U.S., Costa Rica, and Panama; very common North and Central cajennense, Amblyomma and widely distributed in A. americanum America oblongoguttatum, Amblyomma ovale, ticks in the U.S., with avg infection Rhipicephalus microplus, Rhipicephalus frequencies of40-70%; pathogenic potential sanguineus, Dermacentor nitens, unknown Amblyomma maculatum Amblyomma cajennense, Amblyomma Possibly associated with animal infection in South America coelebs, Amblyomma neumanni, Brazil; also reported in Argentina and Amblyomma longirostre, Amblyomma French Guyana geayi, Amblyomma auricularium

“Candidatus Rickettsia andeanae” Amblyomma maculatum Occurs in A. maculatum ticks in the North and Central southeastern U.S.; recently isolated in cell America culture, but pathogenic potential is unknown Amblyomma maculatum, Amblyomma Reported in ticks from Peru and Chile; in South America parvum, Amblyomma pseudoconcolor, Argentinean ticks, reported as Rickettsia sp. Amblyomma triste, Ixodes boliviensis strain Argentina

Strain ApPR Amblyomma parkeri Reported in bird ticks in Brazil; genetically South America related to R. parkeri, R. africae, and R. sibirica

Rickettsia antechini Ixodes antechini Australia Australia

Strain Aranha Amblyomma longirostre Reported in bird ticks in Brazil; could be R. South America amblyommii

Rickettsia argasii Argas dewae Australia Australia

Rickettsia asiatica Ixodes ovatus, Ixodes pomerantzevi Found in the blood of sika deer in Japan Asia

Rickettsia sp. AvBat Argas vespertilionis Europe

“Candidatus Rickettsia barbariae” Rhipicephalus turanicus Europe

Rickettsia bellii Amblyomma sabanerae, Dermacentor Sporadically distributed throughout the U.S. North and Central occidentalis, Dermacentor variabilis, and described recently in El Salvador; America Dermacentor parumapertus, rabbits and guinea pigs develop eschars Dermacentor albipictus, H. following subcutaneous inoculation; no leporispalustris, Argas cooleyi, known cases of illness in humans concanensis Various species of Amblyomma, Represents a distinct basal group within the South America Haemaphysalis juxtakochi, Ixodes rickettsiae; it is the rickettsia with the greatest loricatus variety of tick hosts in South America; reported in Argentina, Brazil, and Peru

Rickettsia canadensis Haemaphysalis leporispalustris Canada and U.S.; elicits a febrile response in North and Central guinea pigs and rickettsemias of several-days’ America duration in meadow mice and baby chicks; suspected to cause illness in humans, but there have been no confirmed cases

Strain Colombianensi Amblyomma dissimile, Rhipicephalus Reported in Colombia; genetically related to South America microplus R. tamurae and R. monacensis (Continued on following page)

October 2013 Volume 26 Number 4 cmr.asm.org 663 Parola et al.

TABLE 2 (Continued) Rickettsia species or strain Associated tick(s) Comment(s) Geographical distributiona “Candidatus Rickettsia cooleyi” I. scapularis Occurs at very high frequencies and broadly North and Central distributed in I. scapularis ticks across the America eastern, upper Midwestern, and southern U.S.; may represent an endosymbiont

Strain COOPERI Amblyomma dubitatum (reported as Reported in capybara ticks in Brazil; South America Amblyomma cooperi) genetically related to R. parkeri, R. africae, and R. sibirica

Rickettsia sp. strain Davousti Ixodes ricinus, Ixodes lividus Ticks from migratory birds Europe

Rickettsia sp. strain Davousti Amblyomma tholloni Closely related to R. heilongjiangensis Sub-Saharan Africa

Rickettsia derrickii Bothriocroton hydrosauri Australia

Rickettsia sp. strain DmS1 Dermacentor Europe

Rickettsia gravesii sp. nov. Australia

Rickettsia sp. strains G021 and G022 Ixodes pacificus Northern California; possibly identical to North and Central Grants Pass or Tillamook strain isolated in America Oregon and California in the late 1970s and early 1980s; pathogenic potential is unknown

“Candidatus Rickettsia goldwasserii” Haemaphysalis adleri, Haemaphysalis Israel Asia parva

Rickettsia guntherii Haemaphysalis humerosa Australia Australia

Rickettsia hoogstraalii Carios capensis Japan Asia Haemaphysalis punctata, Haemaphysalis Europe sulcata Argas persicus, Sub-Saharan Africa

Rickettsia sp. strain IG-1 Ixodes granulatus Taiwan, Japan Asia

Rickettsia sp. strain IXLI1 Ixodes lividus Closely related to R. japonica Europe

Koala rickettsia Bothriocroton concolor Australia Australia

“Candidatus Rickettsia kotlanii” Ixodid ticks Europe

“Candidatus Rickettsia kulagini” Rhipicephalus sanguineus Europe

Rickettsia sp. clone KVH-02-3H7 Ixodes ricinus Europe

“Candidatus Rickettsia liberiensis” Ixodes muniensis Closely related to R. raoultii Sub-Saharan Africa

Rickettsia montanensis Dermacentor andersoni U.S. and Canada; no known cases of illness in North and Central Dermacentor variabilis humans America Amblyomma americanum

Rickettsia monteiroi Amblyomma incisum Recently described in Brazil; joined to R. bellii South America and R. canadensis in the most basal group of tick-associated rickettsiae

“Candidatus Rickettsia moreli” Ixodes ricinus Europe

Strain NOD Amblyomma nodosum, Amblyomma Reported in bird ticks in Brazil; genetically South America calcaratum, Amblyomma longirostre related to R. parkeri, R. africae, and R. sibirica (Continued on following page)

664 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

TABLE 2 (Continued) Rickettsia species or strain Associated tick(s) Comment(s) Geographical distributiona Strain Pampulha Amblyomma dubitatum Reported in Brazil; genetically related to R. South America tamurae and R. monacensis

Rickettsia sp. strain Parumapertus Dermacentor parumapertus Western U.S.; causes mild to moderately North and Central severe disease in guinea pigs America

Rickettsia peacockii Dermacentor andersoni Western U.S. and Canada; closely related to North and Central R. rickettsii but considered a America nonpathogenic endosymbiont

“Candidatus Rickettsia principis” Haemaphysalis japonica douglasi, Russian Far East, northeastern China Asia Haemaphysalis danieli

Rickettsia sp. RDla440 Dermacentor auratus Thailand Asia

Rickettsia sp. RDla420 Dermacentor spp. Thailand Asia

Rickettsia rhipicephali Rhipicephalus haemaphysaloides Taiwan Asia Rhipicephalus sanguineus Rhipicephalus lunulatus, Rhipicephalus Sub-Saharan Africa composites group Rhipicephalus sanguineus, Dermacentor U.S.; causes moderately severe illness when North and Central occidentalis, Dermacentor variabilis, inoculated into meadow voles; no known America Dermacentor andersoni cases of illness in humans Haemaphysalis juxtakochi Infects ticks from the Brazilian Amazon and South America Atlantic rainforests

“Candidatus Rickettsia rioja” Dermacentor marginatus Europe

Rickettsia sauri Amblyomma hydrosauri Australia Australia

“Candidatus Rickettsia siciliensis” Rhipicephalus turanicus Europe

“Candidatus Rickettsia tarasevichiae” Ixodes persulcatus Russia and Japan Asia

Rickettsia tasmanensis Ixodes tasmani Australia Australia and Pacific

Rickettsia sp. strain Uilenbergi Amblyomma tholloni Closely related to the R. massiliae group Sub-Saharan Africa

“Candidatus Rickettsia vini” Ixodes arboricola, Ixodes ricinus Europe

Rickettsia sp. Rhipicephalus (Boophilus) spp. Laos Asia

Rickettsia sp. Ixodes persulcatus Northern China Asia

Rickettsia sp. Rhipicephalus turanicus Closely related to but distinct from the R. Europe rhipicephali-R. massiliae lineage

Rickettsia sp. Ixodes ricinus Sister taxon of R. bellii Europe

Rickettsia sp. Ixodes ricinus High homology with R. limoniae Europe

Rickettsia sp. Ixodes ricinus Sister taxon of R. bellii Europe

Rickettsia sp. Rhipicephalus evertsi Closely related to the R. rickettsii group Sub-Saharan Africa

Rickettsia sp. Rhipicephalus sanguineus, Haemaphysalis North Africa erinacei

Rickettsia sp. from A. tuberculatum Amblyomma tuberculatum Southern U.S.; genetically similar to R. North and Central (148) parkeri, R. africae, and R. sibirica; America pathogenic potential unknown a See figures.

October 2013 Volume 26 Number 4 cmr.asm.org 665 Parola et al.

TABLE 3 Main characteristics of currently available tick-borne Rickettsia genomesa Chromosome No. of GϩC Noncoding No. of plasmids GenBank accession Species Strain Rickettsiosis size (kb) ORFs content (%) DNA (%) (size [kb]) no. R. africae ESF-5 African tick bite fever 1,278,540 1,260 32.4 28 1 (12.4) CP001612

R. australis Phillips Queensland tick typhus 1,297,390 1,110 31.7 26 2 (26.6 and AKVZ00000000 30.1) Cutlack Queensland tick typhus 1,296,670 1,297 32.3 NA 1 (26.6) CP003338

R. bellii OSU 85-389 Unknown pathogenesis 1,528,980 1,470 32 20 0 CP000849 RML369-C 1,522,076 1,429 31.7 14.8 0 CP000087

R. canadensis McKiel Unknown pathogenesis 1,159,722 1,129 31.1 26 0 CP000409 CA410 Unknown pathogenesis 1,150,228 1,052 31 NA 0 CP003304

R. conorii subsp. conorii Malish Seven Mediterranean spotted fever 1,268,755 1,374 32.4 19 0 AE006914

R. conorii subsp. indica ITTR Indian tick typhus 1,249,482 1,157 32.5 19.1 0 AJHC00000000

R. conorii subsp. caspia A-167 Astrakhan fever 1,260,331 1,210 33 18.8 0 AJUR00000000

R. conorii subsp. ISTTCDC1 Israeli spotted fever 1,252,815 1,164 32 20.0 0 AJVP00000000 israelensis

R. heilongjiangensis 054 Far-Eastern tick-borne 1,278,471 1,297 32.3 17 0 CP002912 rickettsiosis

R. helvetica C9P9 Unnamed rickettsiosis 1,369,827 1,135 32.2 15.9 1 (47.1) CM001467

R. honei RB Flinders Island spotted fever 1,268,758 1,284 32.4 19 0 AJTT00000000

R. japonica YH Oriental spotted fever 1,331,743 1,239 32.7 28 1 (19.8) AMRT00000000 YH Oriental spotted fever 1,283,087 1,010 32.4 NA 0 AP011533

R. massiliae Mtu5 Unnamed rickettsiosis 1,360,898 1,436 32.5 31 1 (15.2) CP000683 AZT80 Unknown pathogenesis 1,263,719 1,243 32.6 NA 1 (15.0) CP003319

R. montanensis OSU 85-930 Unknown pathogenesis 1,279,798 1,254 32.6 NA 0 CP003340

R. parkeri Portsmouth R. parkeri rickettsiosis 1,300,386 1,354 32.4 NA 0 CP003341

R. peacockii Rustic Unknown pathogenesis 1,288,492 984 33 NA 1 (26.4) CP001227

R. philipii 364D Unnamed rickettsiosis 1,287,740 1,380 32.5 NA 0 CP003308

R. raoultii RpA4 SENLAT 1,275,089 1,355 32.5 15.4 3 (20.8, 34.5, CP002428 and 83.2)

R. rhipicephali 3-7-female6-CWPP Unknown pathogenesis 1,290,368 1,302 32.4 NA 1 (15.0) CP003342

R. rickettsii Sheila Smith Rocky Mountain spotted fever 1,257,710 1,382 32.4 24 0 NC_009882 Iowa Avirulent 1,268,175 1,421 32.4 NA 0 NC_010263 Arizona Rocky Mountain spotted fever 1,267,197 1,380 32.4 NA 0 CP003307 Brazil Rocky Mountain spotted fever 1,255,681 1,369 32.5 NA 0 CP003305 Colombia Rocky Mountain spotted fever 1,270,083 1,387 32.5 NA 0 CP003306 Hlp#2 Unknown pathogenicity 1,270,751 1,345 32.5 NA 0 CP003311

R. sibirica subsp. sibirica BJ-90 Siberian tick typhus 1,254,013 1,182 32.5 17.5 0 AHIZ00000000 246 1,250,021 1,151 32.5 17.3 0 AABW00000000

R. sibirica subsp. HA-91 Lymphangitis-associated 1,252,337 1,138 32.4 18.5 0 AHZB00000000 mongolitimonae rickettsiosis

R. slovaca 13-B Tick-borne lymphadenitis 1,275,089 1,323 32.5 18.7 0 CP002428 D-CWPP Tick-borne lymphadenitis 1,275,720 1,386 32.5 NA 0 CP003375

Rickettsia endosymbiont Unknown pathogenesis 1,821,709 2,059 31 22 4 (33.9, 49.8, NZ_ACLC00000000 of Ixodes scapularis 55.1, and 66.8) a ORFs, open reading frames; NA, not applicable.

666 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 1 Genome sequence-based phylogenetic tree of Rickettsia species. This tree was constructed by aligning the 597 orthologous genes of all studied genomes. Phylogenetic relationships were inferred by using the parsimony method. gene transfer (LGT) could occur among rickettsiae (16, 17). In or amplifiers of rickettsiae in nature. In the last decade, the rela- fact, several LGT candidates were identified among Rickettsia ge- tionship between Rickettsia conorii subsp. conorii and its tick host nomes, including tra and pat2, genes encoding type IV secretion was called into question based on the lethal effect of this species of system proteins and ATP/ADP translocases, respectively (1). Re- Rickettsia on Rhipicephalus sanguineus, the brown dog tick, in ex- cently, Merhej et al. identified 165 rickettsial genes that may have perimental models of infection (20, 21). The reasons for this re- been acquired by R. felis from R. bellii; R. typhi; other bacteria, duction in fitness were shown to be unrelated to the geographical including Legionella sp. and Francisella sp.; or even eukaryotes origin of the ticks (22) and to the inoculation methods (20, 23). (18)(Fig. 1). Some of these genes appear to have been transferred However, when naturally infected Rhipicephalus sanguineus indi- in blocks containing several genes. Finally, investigators have viduals were used (24), larvae, nymphs, and adults were main- identified 13 chimeric genes in R. felis that were the result of re- tained under laboratory conditions over several generations with a combinations with R. typhi genes (18), thus offering a consider- transovarial transmission (TOT) rate (the percentage of infected ably more diversified genetic picture of rickettsiae than previously females that pass microorganisms to their progeny) that reached expected. 100% and a filial infection rate (FIR) (the percentage of infected progeny derived from an infected female) of nearly 99% (25). RELATIONSHIP BETWEEN SPOTTED FEVER GROUP Similarly, two studies in Brazil obtained a Ͻ50% FIR of R. rickett- RICKETTSIAE, IXODID TICKS, AND VERTEBRATE HOSTS sii in Rhipicephalus sanguineus and Amblyomma cajennense tick Ixodid ticks are the main vectors of SFG rickettsiae (Fig. 2). The colonies experimentally infected with an in vitro-cultured strain of tick-rickettsia relationship has been a point of interest for many R. rickettsii (26, 27), while another Brazilian study reported a researchers, and most studies concentrate on the role of ticks as 100% FIR of R. rickettsii in naturally infected Rhipicephalus san- vectors. Unfortunately, less attention has been directed toward the guineus ticks (28). Interestingly, 100% TOT and 100% FIR of R. relationship among rickettsia and tick cells, tissues, and organs. rickettsii were described for experimentally infected Amblyomma Rickettsiae have developed many strategies to adapt to different aureolatum ticks through 4 laboratory generations (29). However, environmental conditions, including those within their arthropod lower reproductive performance and survival of infected female vectors and vertebrate hosts (19). Many species of the genus Rick- ticks were attributed to R. rickettsii infection. The authors hypoth- ettsia are considered to be vertically transmitted symbionts of in- esized that these results may explain the low infection rates (Ͻ1%) vertebrates, suggesting that the arthropod vectors act as reservoirs usually reported among field populations of A. aureolatum ticks in

October 2013 Volume 26 Number 4 cmr.asm.org 667 Parola et al.

Recently, an analysis of all of the sequences in the toxin-anti- toxin (TA) database of 33 published genomes showed a significant link between vertical transmission and the presence of genomic copies of TA genes and modules (35). This significant statistical relationship suggests that TAs play a role in the mainte- nance of Rickettsia in their arthropod hosts via a mechanism that is currently unknown. The persistence of mobile TA genes in the genomes of some Rickettsia might reflect an obligate connection of the bacteria and their host cell (35). Vertical transmission of rickettsiae in helps to maintain the infection in nature, but for some rickettsial agents, a life cycle including infected arthropods and one or more rickett- sial host is required to guarantee survival of the bacteria in nature (36). To date, very few data are available regarding the animal reservoirs of these bacterial species, with the exception of R. rickettsii and Rickettsia sibirica subsp. sibirica, which were isolated from vari- ous wild mammals (2,36). In 2012, it was shown that dogs are capable of acquiring R. conorii subsp. israelensis from infected Rhipicephalus sanguineus ticks and transmitting bacterial infection to cohorts of uninfected ticks, thus confirming for the first time that dogs can act as competent reservoirs for these bacteria (37). However, dogs with dif- ferent genetic backgrounds appear to differ in their susceptibility to Rickettsia conorii subsp. israelensis infection (38). Recent studies of experimental infections of capybaras (Hydrochoerus hydrochaeris), opossums (Didelphis aurita), and domestic dogs with a highly viru- lent strain of R. rickettsii showed that these animals developed rick- ettsemia of sufficient magnitude to infect A. cajennense or Rhipiceph- alus sanguineus ticks during feeding (26, 28, 39, 40). These authors suggested that these vertebrate hosts could play an important role as amplifier hosts of R. rickettsii for ticks in nature. With regard to other Rickettsia species, molecular and serological studies have suggested some potential animal reservoirs; however, further studies need to be performed to confirm these hypothesized reservoirs, such as cattle for R. africae (41), wild boars and domestic ruminants for Rickettsia slo- FIG 2 Three tick vectors of spotted fever group rickettsioses. From top to bottom vaca (42, 43), and sika deer for Rickettsia helvetica (44). are Rhipicephalus sanguineus, the primary vector of R. conorii subsp. conorii, the agent of Mediterranean spotted fever; Dermacentor marginatus, vector of R. slovaca Humans are only occasional hosts for ticks and should be viewed and R. raoultii; and Amblyomma variegatum, vector of R. africae, the agent of as a ‘‘dead-end’’ host, which plays no role in maintaining these bac- ATBF. Males are on the left side, and females are on the right. Bar scale, 1 mm. teria in nature (19). In humans, the site of bacterial entry sometimes develops into a localized inflammatory and necrotic skin lesion with areas of Brazil where Rocky Mountain spotted fever (RMSF) is en- a black crust, termed an inoculation eschar (“tache noire”). It repre- demic. The same hypothesis was previously discussed to account for sents the first site of challenge between the human host and the bac- the prevalence of infected R. conorii subsp. conorii ticks in the Medi- terium. The presence of a tache noire is associated with Rickettsia terranean (20); later, these same authors demonstrated that temper- species that contain a large number of TA genes in their genomes. The ature variation could directly affect infected tick vectors and that in- toxic effect of TAs may increase the local reaction, thus inhibiting the fected, quiescent ticks may not survive the winter (25). spread of rickettsia organisms, which is associated with a fatal out- Regarding other Rickettsia species, it is interesting to note that come of this infection. The presence of TAs is significantly inversely studies using naturally infected, engorged females demonstrated correlated with human host mortality (35). Also, it has been specu- 100% TOT and 98.5% FIR of Rickettsia massiliae in Rhipicephalus lated that skin eschar is the reflection of a local control avoiding ex- turanicus ticks (22), 100% TOT and 93.4% FIR of Rickettsia africae treme virulence (45). in Amblyomma variegatum ticks (30), 100% TOT and FIR of Rick- ettsia bellii in Ixodes loricatus (31), and 100% TOT and FIR of TICK-BORNE RICKETTSIAE IN THE AMERICAS “Candidatus Rickettsia amblyommii” in Amblyomma auricu- larium ticks (32). Interestingly, there is some evidence to indicate North and Central America that some typhus group rickettsiae, particularly , Species identified as pathogens. (i) Rickettsia rickettsii. R. rick- the louse-borne agent of , may, under certain cir- ettsii, the etiologic agent of Rocky Mountain spotted fever cumstances, be associated with ticks (33). Additionally, R. felis, the (RMSF), is distributed broadly, albeit at a low frequency, in hard agent of the so-called flea-borne spotted fever, has also been detected ticks throughout the Western Hemisphere (2). In North and Cen- in a various nonhematophagous and hematophagous arthropod spe- tral America, confirmed cases of RMSF have been documented in cies, including soft and hard ticks (34). The role of ticks in the life cycle Canada, the United States, Mexico, Panama, and Costa Rica (46– of these two Rickettsia species remains to be examined. 51)(Fig. 3 and 4). Fatal human infections caused by a SFG Rick-

668 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 3 Tick-borne rickettsiae in North America (except Mexico). Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.) ettsia species, presumably R. rickettsii, have also recently been de- other racial groups (62, 63), related at least in part to the ecological scribed in Guatemala (52). Surprisingly, no confirmed cases of dynamics created by large numbers of Rhipicephalus sanguineus RMSF have been reported from the Caribbean, despite the pres- and free-roaming dogs in peridomestic environments (64). ence of recognized tick vectors in this region. In the United States, The annual incidence of RMSF has undergone 3 dominant RMSF still occurs predominantly in the Midwestern and south- shifts in the United States since national surveillance of this disease eastern states, including Oklahoma, Missouri, Arkansas, Tennes- was initiated in 1920 (53). The reasons for these shifts are largely see, and North Carolina. Approximately two-thirds of the 11,531 speculative; however, the emergence and flux of RMSF and other cases of RMSF reported during 2000 to 2007 originated from these tick-borne diseases described below can most often be traced to five states (53). specific human activities and behaviors that disrupt ecosystems In Mexico, RMSF has been reported in the states of Baja Cali- and place greater numbers of susceptible hosts into the environ- fornia, Sonora, Sinaloa, Durango, Coahuila, and Yucatán. Hyper- ment (65). Because some cases reported as RMSF might actually endemic foci have been described repeatedly in communities in be diseases caused by other SFG rickettsiae, the surveillance case the American Southwest and northern Mexico, linked directly to definition for RMSF in the United States was modified in 2010 to large numbers of R. rickettsii-infected Rhipicephalus sanguineus encompass the broader category of spotted fever rickettsiosis. The ticks that result from unchecked populations of stray and free- number of reported cases of spotted fever rickettsiosis in the ranging dogs (54–61). During 1999 to 2007, the overall U.S. inci- United States, including cases of RMSF, rose 9% during 2009 to dence of RMSF and the case-fatality rate were approximately 4 2010, from 1,815 to 1,985 (66–70). times higher among American Indians than among members of Epidemiologically important vectors of R. rickettsii in North

FIG 4 Tick-borne rickettsiae in Mexico and Central America. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.)

October 2013 Volume 26 Number 4 cmr.asm.org 669 Parola et al.

thy, and gangrene (46, 86, 87). Despite the current availability of an effective treatment and advances in medical care, an estimated 5% to 10% of U.S. patients die when infected with R. rickettsii (48, 61, 87). For unknown reasons, case-fatality rates in Central Amer- ica are considerably higher: estimates from recent outbreaks in Mexico are as high as 38% (88–91), and the case-fatality rate of 6 documented RMSF cases in Panama during 2004 to 2007 was 100% (50, 92). Molecular analysis of 35 historical and contemporary isolates of R. rickettsii identified 5 phylogenetic clades based on sequence polymorphisms in several intergenic regions (93). Specific geo- graphical and vector tick associations were identified among these groups, including clades with associated Amblyomma ticks from Central and South America and clades characterized by D. ander- soni ticks in the northwestern United States. These data also sug- gest that certain isolates, particularly of serotypes Hlp and 364D, are sufficiently different to warrant unique species or subspecies status (94). (ii) Rickettsia parkeri. The first confirmed human infection with R. parkeri was reported in 2004, and approximately 15 cases FIG 5 Petechial rash on a patient with Rocky Mountain spotted fever caused of R. parkeri rickettsiosis have been described in the literature by Rickettsia rickettsii. since that initial report (66–70). In the United States, Amblyomma maculatum (the Gulf Coast tick) is the principal vector for these bacteria, and R. parkeri is detected in 8% to 43% of questing adult and Central America include the Rocky Mountain wood tick A. maculatum ticks collected in states along the Gulf Coast and the (Dermacentor andersoni), the American dog tick (Dermacentor southern Atlantic region (95–101). R. parkeri is distributed variabilis), the Cayenne tick (Amblyomma cajennense), and the throughout multiple tissues of infected A. maculatum ticks, in- brown dog tick (Rhipicephalus sanguineus)(49, 71); however, R. cluding the salivary glands, the midgut, the Malpighian tubules, rickettsii is found occasionally in other ticks, including the lone and the ovaries (102). R. parkeri is detected infrequently in A. star tick (Amblyomma americanum) in the United States, Ambly- americanum (103) and D. variabilis (79, 104). Infections of dogs omma imitator in Mexico, Dermacentor nitens in Panama, and and cows caused by R. parkeri have been reported in the south- Haemaphysalis leporispalustris in Costa Rica, all of which may oc- eastern United States (105, 106). casionally be involved in the transmission of this pathogen to hu- In most cases of R. parkeri infection, a necrotic inoculation mans and animals (51, 72–75). Contemporary molecular surveys eschar forms several days following the bite of an infected tick, for R. rickettsii in North American Dermacentor ticks reveal ex- preceding a low to moderate fever in several days. R. parkeri rick- tremely low frequencies of occurrence of these bacteria in ticks, ettsiosis is milder than RMSF, and no severe systemic manifesta- characteristically Ͻ0.5% (76–80). However, unusually large num- tions or deaths have been described (67–69). It is likely that some bers of R. rickettsii-infected Rhipicephalus sanguineus ticks are a U.S. cases that were previously categorized as RMSF should have hallmark of several hyperendemic foci of RMSF in the United been classified as R. parkeri rickettsiosis (66, 71, 107, 108). No States and Mexico (54, 56, 81–83), suggesting that Rhipicephalus cases of R. parkeri rickettsiosis have been reported in Central sanguineus may be a more important vector of RMSF in North and America; however, A. maculatum occurs throughout this region, Central America than previously recognized. To date, Rhipiceph- and a mild, eschar-associated rickettsiosis that is compatible with alus sanguineus has been shown to be an important vector of R. parkeri rickettsiosis was reported recently for a traveler return- RMSF only in the southwestern United States and northern Mex- ing from Honduras (109). ico, possibly due to environmental conditions, the presence of a (iii) Rickettsia massiliae. The first description of R. massiliae in large feral dog population, and/or other animal reservoirs there, North America was reported in 2006, when this SFG rickettsia was and not necessarily an important vector throughout North Amer- detected in adult Rhipicephalus sanguineus ticks collected from a ica. Recent data also indicate that many tick species may be in- hyperendemic focus of RMSF in the southwestern United States fected simultaneously with multiple SFG rickettsiae, including R. (110). This agent was subsequently identified in questing and at- rickettsii (74, 84). tached specimens of Rhipicephalus sanguineus recovered from Patients with RMSF experience an abrupt onset of high fever dogs in California and North Carolina (99, 111). The distribution that is often accompanied by headache, nausea, vomiting, an- and frequency of this bacterial species in brown dog ticks in North orexia, and generalized myalgia. Only rarely is an eschar identified and Central America are poorly described; however, preliminary at the infection site (85). A rash begins on the second to fourth day studies suggest that its New World occurrence is somewhat spo- following the appearance of fever. This rash appears as small pink radic and focal (82, 111, 112). No confirmed human infections macules, typically on the wrists, ankles, and forearms, and evolves have been documented in the United States or Central America, to maculopapules. These lesions evolve into petechiae or purpura although R. massiliae has been putatively linked to mild to mod- in 50% to 60% of patients (Fig. 5). Severe manifestations might erately severe illnesses in dogs in California (111). include pulmonary edema and hemorrhage, cerebral edema, (iv) Rickettsia africae. African tick bite fever (ATBF) caused by myocarditis, renal failure, disseminated intravascular coagulopa- R. africae is distributed broadly across most of the African conti-

670 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World nent (see below). It was first described in the Western Hemisphere of the genus Rickettsia (121). R. canadensis elicits a febrile response in 1998 in a patient from Guadeloupe in the West Indies (113). in guinea pigs and produces rickettsemias of several days’ duration Since that report, the pathogen has been detected in Amblyomma in meadow mice and baby chicks. Human infections are suggested variegatum ticks collected from 8 additional territories and coun- from several serologic studies of ill patients; however, no con- tries in the Caribbean, including Martinique, Dominica, Montser- firmed cases of the disease have been identified. rat, Nevis, St. Kitts, St. Lucia, Antigua, and the U.S. Virgin Islands (iii) Rickettsia montanensis. R. montanensis, first described in (113). Tick surveys on these islands revealed R. africae infection 1961 in Dermacentor ticks collected in eastern Montana, is identi- rates that range from 7% to 62% (114, 115). An important aspect fied with various frequencies in D. variabilis and D. andersoni ticks for the epidemiology of ATBF is the acquisition of the disease by throughout North America. Its occurrence in populations of D. North American tourists, hunters, or deployed military members variabilis ticks collected from 15 locations in 4 different provinces returning from areas where R. africae is endemic (116–118). The of Canada ranged from 0 to 33% (77). In many parts of the eastern disease begins approximately 5 to 7 days following a tick bite, with United States, R. montanensis is the predominant rickettsial spe- an abrupt onset of fever, fatigue, headache, and myalgia. Inocula- cies detected in D. variabilis ticks (80). Approximately 10% to 17% tion eschars are reported inconsistently and are identified in ap- of questing and attached specimens of D. variabilis collected from proximately 50% to 100% of cases; however, the occurrence of Florida, Georgia, and Tennessee contain this SFG rickettsia (78, multiple eschars is relatively frequent. Other common features 122). R. montanensis has also been reported occasionally in A. include regional lymphadenopathy, a generalized maculopapular americanum ticks (78). There are no reports of confirmed disease or papulovesicular rash, and, occasionally, aphthous stomatitis. in humans caused by R. montanensis; however, a recent descrip- No cases of fatal disease resulting from these bacteria have been tion of a child with an afebrile, rash-associated illness and sero- reported, although more severe manifestations, including myo- conversion to R. montanensis antigens following the bite of an R. carditis and neuropathy, are sometimes described. montanensis-infected D. variabilis tick suggests that this SFG Rick- (v) Rickettsia philipii (Rickettsia 364D). In 2008, the first hu- ettsia may cause a mild, spotted-fever-like illness in some patients man infection with “Rickettsia 364D” was confirmed in a patient (123). from northern California. Rickettsia 364D, an as-yet-unclassified (iv) Rickettsia peacockii. R. peacockii, an endosymbiont of D. SFG rickettsia initially described in 1975 from an isolate obtained andersoni ticks in the western United States and Canada, was likely from Dermacentor occidentalis ticks collected in southern Califor- recognized as early as 1925 but was not formally characterized nia, has been detected in approximately 8% of the questing D. until 1997. The infection frequency of R. peacockii in D. andersoni occidentalis ticks throughout California (76–80). Because R. rick- is often high: this SFG rickettsia was detected in 76% of 508 ticks ettsii is rarely identified in human-biting ticks in this state, it has collected from 9 localities in Canada (77) and in as many as 80% of been suggested that Rickettsia 364D, provisionally named “Rick- D. andersoni ticks collected from the eastern side of the Bitterroot ettsia philipii”(94), is responsible for many of the illnesses in this Valley of Montana. Also referred to as the East Side agent, R. region that resemble and are misdiagnosed as RMSF. In addition peacockii occurs almost exclusively within the oocytes and inter- to the index patient, three suspected cases have been described, stitial cells of D. andersoni ticks, interfering with the ability of R. each with an eschar and mild constitutional complaints that vari- rickettsii to infect these tissues (124). It has been proposed that R. ably include fever, headache, myalgia, and fatigue (119). rickettsii or another closely related pathogenic SFG rickettsia un- Species of unknown pathogenicity. (i) Rickettsia bellii. R. bel- derwent various changes in its genome to become R. peacockii. lii was first isolated in 1966 from D. variabilis ticks collected in Potential virulence genes deleted or mutated in R. peacockii in- Arkansas, and many other tick host species for this bacterium were clude those coding for an ankyrin repeat-containing protein, subsequently detected, including D. andersoni, D. occidentalis, DsbA, RickA, protease II, OmpA, and a putative phosphoeno- Dermacentor albipictus, Dermacentor parumapertus, Haemaphys- lamine transferase (125, 126). alis leporispalustris, and the soft ticks Ornithodoros concanensis and (v) Rickettsia rhipicephali. R. rhipicephali was first described in Argas cooleyi (120). This Rickettsia species appears to be distrib- 1975 following its isolation from Rhipicephalus sanguineus ticks uted sporadically: it has been detected in as many as 80% of the collected in Mississippi. It has been identified sporadically in D. isolates obtained from D. variabilis ticks in Ohio and North Car- occidentalis, D. andersoni, and D. variabilis ticks across the United olina but occurs in fewer than 1% of the California Dermacentor States (76). The pathogenic potential of R. rhipicephali in humans ticks recently evaluated for SFG rickettsiae by molecular assays. R. is unknown but is suggested by the moderately severe disease elic- bellii also occasionally appears in mixed infections of ticks with R. ited in experimentally inoculated meadow voles (66). rickettsii, Rickettsia rhipicephali,orRickettsia montanensis (76, 84). Nonvalidated, incompletely described, or uncultivated spe- For decades, R. bellii was characterized as a nonpathogenic organ- cies. “Candidatus Rickettsia amblyommii” was first documented ism; however, subcutaneous inoculation of this rickettsia pro- in 1981 and has since been identified as a commonly occurring duces eschars in rabbits and guinea pigs (16), suggesting that its and widely distributed SFG rickettsia in A. americanum ticks role as a potential pathogen of humans deserves further consider- (127–129). “Candidatus Rickettsia amblyommii” produces a gen- ation. eralized infection in A. americanum that is distributed throughout (ii) Rickettsia canadensis. R. canadensis was initially isolated multiple tissues, including the salivary glands, midgut, and ovaries from a pool of Haemaphysalis leporispalustris ticks collected from (130). Contemporary surveys of questing adult A. americanum Ontario, Canada, in 1962 and subsequently from specimens of ticks collected from several states in the eastern United States re- Haemaphysalis leporispalustris collected from California in 1980. ported average infection frequencies of 45% in Georgia, 66% in Recent phylogenetic analyses suggest that R. canadensis, similarly Maryland, 13% in New Jersey, 42% in New York, and 60% in to R. bellii, shares some characteristics with both the typhus group North Carolina (131–134). Infections have also been detected and the SFG rickettsiae and may closely resemble ancestral forms commonly in larval-stage ticks (78, 127, 135, 136). “Candidatus

October 2013 Volume 26 Number 4 cmr.asm.org 671 Parola et al.

Rickettsia amblyommii” occurs in several other North American the “Candidatus Rickettsia” species from A. tuberculatum in ver- ticks, including D. variabilis, A. maculatum, and A. cajennense (78, tebrate hosts is unknown (148). 80, 97, 99, 104, 122, 137). In Central America, “Candidatus Rick- There are no confirmed reports of natural transmission of a ettsia amblyommii” has been identified in A. cajennense ticks from pathogenic Rickettsia species to humans by an argasid tick. How- Costa Rica and Panama (138, 139) and in D. nitens, Amblyomma ever, specimens of Ornithodoros parkeri and Ornithodoros rostra- oblongoguttatum, Amblyomma ovale, Rhipicephalus (Boophilus) tus, when infected experimentally with R. rickettsii, are capable of microplus, and Rhipicephalus sanguineus ticks in Panama (72, 139, later transmitting the infection to susceptible animals, suggesting 140). “Candidatus Rickettsia amblyommii” has been implicated as a possible role for soft ticks as vectors of one or more SFG rickett- a possible cause of mild or subclinical infection in humans in the siae. An uncharacterized SFG rickettsia (GenBank accession num- United States (137, 141); however, neither guinea pigs, meadow bers AY763101 and AY63102), closely related to Rickettsia pea- voles, nor rabbits exhibit any evidence of disease when inoculated cockii and R. rickettsii, has been detected recently in specimens of with this SFG rickettsia (130), and there is no evidence of direct the argasid tick Carios kelleyi collected in Iowa (149). This SFG detection of “Candidatus Rickettsia amblyommii” in human clin- agent has not been isolated in culture, and its pathogenic potential ical specimens (142). is unknown. “Candidatus Rickettsia andeanae” was first documented in North America in 2010 in A. maculatum ticks collected in Florida South America and Mississippi (96). Since then, this SFG rickettsia has been iden- Species identified as pathogens. (i) Rickettsia rickettsii. R. rick- tified throughout the U.S. range of A. maculatum ticks, occurring ettsii is the most important tick-borne zoonotic agent in South sympatrically with but typically at frequencies considerably lower America (Fig. 6), where it was first reported in Brazil during the than those of R. parkeri (98–101, 143). Coinfections of A. macu- 1920s. Although RMSF is the typical name of the disease caused by latum ticks with R. parkeri and “Candidatus Rickettsia andeanae” R. rickettsii, in Brazil, it has been referred to as Brazilian spotted have been reported (100, 101). The pathogenic potential of “Ca. fever since the first half of the past century (150, 151). Human Rickettsia andeanae” is unknown; however, the recent isolation of cases of RMSF have also been reported in Argentina and Colombia this bacterium in cell culture should allow for a more detailed (152, 153). In Colombia, the disease was first reported as a large analysis including species characterization and a better under- outbreak during the 1930s, when 62 (95%) out of 65 affected standing of its capacity to elicit disease in vertebrate hosts (144). people succumbed to the infection. Thereafter, it remained unre- “Candidatus Rickettsia cooleyi” is commonly encountered in ported for more than 65 years, followed by recent outbreaks dur- populations of Ixodes scapularis ticks across the United States (78, ing the last 6 years in different parts of Colombia (154). Therefore, 104, 122). In some areas, it is detected in 90% to 100% of I. scapu- it is possible that RMSF remains unreported in other South Amer- laris ticks (104, 145, 146), suggesting that this species is an endo- ican countries where diagnostic tools are absent and where the symbiont. Other incompletely described SFG rickettsiae that have disease is clinically misdiagnosed as several other acute hemor- been detected in I. scapularis include Rickettsia sp. strain Is-1 rhagic diseases. Similarly, the clinical illness caused by R. rickettsii (GenBank accession number DQ34462) and Rickettsia sp. strain in domestic dogs may often remain unreported in many parts of TR-39 (accession number DQ480762)(122). South America. Although North American studies have shown for Two unique SFG phylotypes, designated G021 and G022, have decades that R. rickettsii is also pathogenic in dogs, the occurrence been identified in Ixodes pacificus ticks collected in California of RMSF in dogs was only recently reported in Brazil (155). (147). Rickettsia sp. G021 forms part of a clade that includes Rick- General symptoms caused by R. rickettsii in South America are ettsia akari, Rickettsia australis, and the I. scapularis endosymbiont similar to those in the United States. Severe clinical manifestations TX125 (GenBank accession number EF68975.1). Rickettsia sp. seem to be more frequently reported, usually associated with a G022 appears to be closely related to several pathogenic SFG rick- higher case-fatality rate, and include jaundice, central nervous ettsiae, including R. sibirica subsp. sibirica, R. conorii, and R. system impairment, respiratory distress, and acute renal insuffi- parkeri. It is possible that these phylotypes represent the previ- ciency (150, 151). While the general case-fatality rate is currently ously described Rickettsia strains Tillamook and Grants Pass, approximately 20 to 40% (150, 156), the rate may reach 80% in a which were isolated from I. pacificus ticks collected in Oregon and few areas where diagnostic suspicion and specific antibiotic ther- California during the late 1970s and early 1980s, respectively (2, apy are delayed (157). Indeed, the higher incidences of other hem- 66). The Tillamook strain causes fever and scrotal swelling in orrhagic manifestations endemic to South American countries, guinea pigs and may be lethal to mice, suggesting that it may play such as dengue, leptospirosis, and meningitis, are associated with a role as a human pathogen (108). the lack of diagnostic tools for spotted fever rickettsiosis. This may Rickettsia sp. strain Parumapertus is a SFG rickettsia that is result in late diagnostic suspicion of rickettsiosis and, conse- similar to, but distinct from, R. rickettsii. It was initially detected in quently, in more severe advanced cases that rapidly cause fatalities D. parumapertus ticks removed from jackrabbits in the Great Ba- (150). sin of the United States in the 1950s. Isolates of this strain no The main vector of R. rickettsii in Argentina, Brazil, and Co- longer exist for genotypic analyses; however, earlier studies docu- lombia is A. cajennense, which is generally the tick that bites hu- mented mild fever and scrotal swelling in guinea pigs inoculated mans most frequently in South America (158). Frequently, hu- with the agent, suggesting that it holds pathogenic potential for mans are infested by dozens to hundreds of A. cajennense humans (66, 120). ‘“Candidatus Rickettsia” species from A. tuber- specimens in areas where RMSF is endemic; however, the disease culatum ’ was described in 2012 in adult and larval-stage gopher has always had a low incidence, which is related to the low R. tortoise ticks (Amblyomma tuberculatum) collected in Georgia, rickettsii infection rates among ticks under natural conditions, Florida, and Mississippi. The prevalence of infection among these usually Յ1% (159). These low rates may be related to the low specimens ranged from 50% to 100%. The pathogenic potential of ability of A. cajennense to sustain R. rickettsii infection through

672 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 6 Tick-borne rickettsiae in South America. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.) successive generations. One study in Brazil demonstrated that 162, 164–166), and reports have also come from an area where both transstadial and transovarial transmissions of R. rickettsii oc- RMSF is not endemic (167). As it has been shown that R. rickettsii curred in Ͻ50% of infected ticks, in addition to the observed is maintained by transstadial and transovarial transmission in lower reproductive performance of infected female ticks than of Brazilian Rhipicephalus sanguineus ticks (26, 28) and that the do- uninfected ticks (27). Therefore, it is believed that such areas mestic dog is an efficient amplifier host of R. rickettsii in Rhipi- where RMSF is endemic are highly dependent on the availability cephalus sanguineus ticks (26), studies are needed to elucidate the of amplifier vertebrate hosts, which are animals that maintain the participation of this tick species in the epidemiology of RMSF in bacterium in their circulating blood for some days or weeks at South America. Fortunately, Rhipicephalus sanguineus is not con- levels sufficient to infect new tick cohorts, amplifying rickettsial sidered to be an important human-biting tick in South America infection among the tick population. The systematic presence of (158), which may minimize its role as a primary vector of RMSF in amplifier hosts would guarantee the establishment of this bacte- humans. rium in the tick population for successive generations (159). In (ii) Rickettsia parkeri. In 2004, R. parkeri was reported to infect Brazil, at least two wild vertebrate species, capybaras (Hydrocho- Amblyomma triste ticks in Uruguay (168), at the time when this erus hydrochaeris) and opossums (Didelphis aurita), were recently rickettsia was first confirmed to be a human pathogen in the shown to behave as competent amplifier hosts for A. cajennense United States (see above). Several years later, R. parkeri was found (39, 40). to infect A. triste ticks in Brazil (169) and Argentina (170). Finally, In a few areas of southeastern Brazil, the tick Amblyomma au- in 2011, Romer et al. reported the first human cases of spotted reolatum replaces A. cajennense as the primary vector of R. rickett- fever caused by R. parkeri in Argentina, which were characterized sii (160–162). Interestingly, the transstadial and transovarial by fever, rash, inoculation eschar, lymphadenopathy, and no transmission rates of R. rickettsii in A. aureolatum ticks reach deaths, similar to the clinical illness caused by R. parkeri in the 100%. However, because R. rickettsii is partially pathogenic for United States (68, 171). Similar clinical manifestations, also asso- engorged females of this species, tick infection rates under natural ciated with A. triste, have been reported since the 1990s in Uru- conditions are low, approximately 1% (29, 160). In addition, be- guay, where at least two of these cases were attributed to R. parkeri cause A. aureolatum rarely attacks humans, the incidence of RMSF through cross-absorption (CA) serologic tests (172). is also low in these specific areas of endemicity in southeastern (iii) Rickettsia massiliae. In 2004, R. massiliae was reported to Brazil (163). Finally, a number of recent studies from Brazil re- infect Rhipicephalus sanguineus ticks in Buenos Aires, Argentina ported R. rickettsii infecting Rhipicephalus sanguineus ticks col- (173). Several years later, a patient in Spain was diagnosed with an lected from dogs in areas where RMSF is endemic, where dogs are acute spotted fever illness characterized by fever, a palpable pur- frequently infested by A. aureolatum or A. cajennense ticks (28, puric rash on the upper and lower extremities, and an eschar on

October 2013 Volume 26 Number 4 cmr.asm.org 673 Parola et al. the right leg. Molecular analyses confirmed that the spotted fever and A. coelebs in French Guyana (191). In addition, strains Aranha illness was caused by R. massiliae (174). Because this patient had and AL, which are genetically closely related to “Candidatus Rick- just arrived from Buenos Aires, it was concluded that she had ettsia amblyommii,” have been reported to infect A. longirostre become infected in Argentina, confirming the first case of rickett- ticks in Brazil (189, 190, 192). “Candidatus Rickettsia amblyom- siosis caused by R. massiliae in South America. Recent studies have mii” was shown to be successfully maintained by transstadial and shown that the Rhipicephalus sanguineus populations from the transovarial transmissions through successive generations in A. southern portion of South America are genetically derived from auricularium ticks, which were able to transmit the bacterium to the Mediterranean area (175, 176), where R. massiliae has been laboratory rabbits through larval, nymphal, and adult feeding; reported to infect ticks and humans (177). Therefore, it is possible however, these infections were always asymptomatic (32). Under that the distribution of R. massiliae in the southern portion of natural conditions, there is serological evidence of canine infec- South America is much broader than is currently appreciated. tion by “Candidatus Rickettsia amblyommii” in Brazil (184, 193); (iv) Rickettsia sp. strain Atlantic rainforest or strain Bahia. however, there is no evidence that “Candidatus Rickettsia amblyo- Recently, two cases of spotted fever clinically similar to the disease mmii” is pathogenic for humans or animals. caused by R. parkeri were reported in Brazil. However, both cases “Candidatus Rickettsia andeanae” was first documented in were confirmed to be caused by a newly recognized SFG rickettsia, South America in 2004 in A. maculatum and Ixodes boliviensis ticks strain Atlantic rainforest or strain Bahia, very closely related to R. in Peru (194). Several years later, this rickettsia was reported as parkeri, R. africae, and R. sibirica (178, 179). At the same time, the Rickettsia sp. strain Argentina, from Amblyomma parvum and Atlantic rainforest strain was shown to be associated primarily Amblyomma pseudoconcolor ticks in Argentina (195, 196). More with Amblyomma ovale ticks, the presumed vector of transmission recently, “Candidatus Rickettsia andeanae” was reported from an to humans (180). In addition, A. aureolatum and Rhipicephalus A. triste specimen in northern Chile (197). The pathogenic poten- sanguineus ticks were also found to be infected by this novel bac- tial of “Candidatus Rickettsia andeanae” is unknown. terial strain in the same areas as Rickettsia-infected A. ovale ticks Three distinct rickettsial strains (COOPERI, NOD, and ApPR) (180, 181). It is possible that the occurrence of spotted fever have been reported from different Amblyomma ticks in Brazil caused by the Atlantic rainforest strain is much broader than is (162, 198–200). Indeed, these strains are regarded as potential currently known, as the symptoms of this disease are compatible pathogens because they are phylogenetically related to the patho- with the descriptions of clinical illnesses that have been confirmed gens R. parkeri, R. africae, R. sibirica, and the Atlantic rainforest following seroconversion to spotted fever rickettsial antigens that strain (200). Further studies are necessary to elucidate their taxo- have been reported in other areas of Brazil, where the agent was nomic status because their genetic relatedness to R. parkeri, R. found to infect human-biting ticks, namely, A. ovale and A. aureo- africae, and R. sibirica could justify a subspecies designation. latum (151, 181). The Pampulha strain, recently reported in A. dubitatum ticks Species of unknown pathogenicity. (i) Rickettsia rhipicephali. in Brazil (201–203), and the Colombianensi strain, reported in R. rhipicephali has been reported to infect the tick Haemaphysalis Amblyomma dissimile and Rhipicephalus (Boophilus) microplus juxtakochi in southeastern and northern Brazil (182, 183). There is ticks in Colombia (204), are two distinct strains that are closely serological evidence of canine infection by R. rhipicephali in related to the Old World species Rickettsia tamurae and Rickettsia northern Brazil, but the pathogenic role of this infection remains monacensis. In Brazil, only a few populations of A. dubitatum have unknown (184). been found to be infected by the Pampulha strain; however, infec- (ii) Rickettsia bellii. Despite having been reported in the tion rates are usually very high among the infected populations United States for more than 50 years, R. bellii was first reported in (203). The pathogenic role of these two South American strains is South America in 2004, followed by a number of reports on dif- unknown. Finally, an R. aeschlimannii-like strain was reported in ferent tick species. In Brazil, R. bellii has been reported to infect 11 the tick A. tigrinum in Bolivia (205). Because R. aeschlimannii has tick species, namely, A. ovale, A. oblongoguttatum, A. scalptura- been reported only in the Old World, further studies are needed to tum, A. humerale, A. rotundatum, A. aureolatum, A. dubitatum, elucidate the taxonomic status of this R. aeschlimannii-like strain Amblyomma incisum, A. nodosum, Ixodes loricatus, and Haemaph- from Bolivia. ysalis juxtakochi. It was also reported to infect A. neumanni and A. tigrinum in Argentina and A. varium in Peru, totaling 14 tick spe- TICK-BORNE RICKETTSIAE IN EUROPE cies for the continent (185, 186). While R. bellii has never been associated with human disease, there is serological evidence of Species Identified as Pathogens animal infection in Brazil (187). Rickettsia conorii subsp. conorii. Rickettsia conorii subsp. conorii (iii) Rickettsia monteiroi. R. monteiroi was recently described is the agent responsible for Mediterranean spotted fever (MSF), as having infected the tick A. incisum in an Atlantic rainforest one of the oldest-recognized vector-borne infectious diseases (2). reserve in southeastern Brazil (188). R. monteiroi is genetically MSF is endemic in southern Europe, but sporadic cases have been related to the North American species R. canadensis, and because reported in northern and central Europe, sometimes followed by A. incisum is an important human-biting tick in the Atlantic rain- the installation of a local focus of the disease (2). Rhipicephalus forest biome of southeastern Brazil, the pathogenic role of this sanguineus is the vector and a potential reservoir of R. conorii rickettsia deserves further investigation. subsp. conorii in the Mediterranean area (Fig. 2 and 7)(206). Nonvalidated, incompletely described, or uncultivated spe- However, the excellent fitness of an R. conorii-infected tick labo- cies. “Candidatus Rickettsia amblyommii” was reported to infect ratory colony contrasts with the low prevalence of infected Rhipi- the tick species A. cajennense, Amblyomma coelebs, Amblyomma cephalus sanguineus ticks collected in the wild (Ͻ1%), even in longirostre, Amblyomma geayi, and Amblyomma auricularium in regions of endemicity such as Southern Europe, with the excep- Brazil (32, 189, 190); Amblyomma neumanni in Argentina (185); tion of small foci (25, 177, 207, 208). The influence of extrinsic

674 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 7 Tick-borne rickettsiae in Europe. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.)

factors on infections in diapaused Rhipicephalus sanguineus ticks After an incubation period of approximately 6 days, the onset has been suggested, and infected quiescent ticks may not survive of MSF is abrupt. Recent studies (213, 226, 227) have confirmed the winter (25). Vertebrate reservoirs may play a more dominant that this disease is characterized by fever (94 to 100%), flu-like role in the ecology of R. conorii subsp. conorii than was previously symptoms (78%), prostration (64%), an eschar at the tick bite site appreciated (206). The presence of R. conorii subsp. conorii DNA (53 to 77%), and a rash spreading to the palms and soles (87 to was reported in blood samples from ill dogs (209, 210). A high 96%) that is either maculopapular (94%) or petechial (6%) (Fig. seroprevalence rate (15 to 72%) in dogs has been reported in a 8). In an Italian study of 415 children with MSF, fever, rash, and region where MSF is endemic (211). The proximity to seroreactive eschar were present in 93%, 94.5%, and 63.4% of cases, respec- dogs has been reported as a risk factor for MSF in humans (210). tively, and 4.6% of the children presented atypical exanthema In addition, hedgehogs were suggested to be a potential reservoir (petechial, purpuric, papulovesicular, and vesicular) (228). Mul- for R. conorii subsp. conorii (212). However, the animal reservoir tiple eschars (177, 213, 228–230) and clusters of MSF cases (177) of R. conorii subsp. conorii was never conclusively demonstrated have been reported, which are novel findings for MSF because the (37, 206), and further studies need to be performed. probability of being bitten simultaneously by several infected Rh- In Europe, most MSF cases occur in the summer (2, 213–215). ipicephalus sanguineus ticks is considered rare (177). These emerg- The MSF incidence may increase with higher temperatures, lower ing findings have been linked to the increased aggressiveness and rainfall, and a decrease in the number of days of frost during the propensity of Rhipicephalus sanguineus to bite hosts under preceding year (177, 216, 217). Particularly, this higher incidence warmer conditions, as was shown in animal and human models during warmer months seems to be related to a warming-medi- (177). ated increase in the aggressiveness of R. sanguineus ticks to bite In recent years, atypical and serious life-threatening presen- humans (177). tations of MSF in Mediterranean countries were reported, with Since 2005, in addition to 14 European countries (2), R. conorii cardiac symptoms (ectasia of the coronary arteries, myocardi- was detected in Serbia (218), Romania (219), Slovakia (220), and tis, and atrial fibrillation) (231–233), ocular symptoms (uveitis, Malta (221) by serological methods. The seroprevalences of R. retinopathy, and retinal vasculitis) (177, 234–236), neurological conorii infection were 3.9% in Italy (222), 4.4% in the Canary symptoms (cerebral infarct, meningoencephalitis, sensorineural Islands (Spain) (223), 8.7 to 11.2% in Spain (224, 225), and up to hearing loss, acute quadriplegia secondary to an axonal polyneu- 23% in the Serbian mountain areas (218). Urban populations are ropathy, and motor and sensory polyneuritis) (228, 236–241), as affected as rural populations, regardless of gender (213). pancreatic involvements (242, 243), splenic rupture (244), acute

October 2013 Volume 26 Number 4 cmr.asm.org 675 Parola et al.

cases and severe forms of ISF have been described, especially in children as well as in travelers and those with G6PD deficiency (251–253). Rickettsia conorii subsp. caspia. Rickettsia conorii subsp. caspia is the agent of Astrakhan fever, a summer spotted fever endemic to the Astrakhan region and nearby regions of the Caspian Sea (2). It is transmitted to humans through the bites of Rhipicephalus pumilio ticks. In Europe, this rickettsia was detected in R. san- guineus ticks from Kosovo and, recently, from Southern France (2, 254). Thus, Astrakhan fever might be a cause of spotted fever in Europe, and the area of distribution of this Rickettsia could be broader than the limits of the Astrakhan region, as was initially believed. In recent years, the increased incidence of Astrakhan fever in Russia is explained by the reconfiguration of natural land- scapes as a result of increasing anthropogenic impact (255). Clin- ically, Astrakhan fever is similar to MSF, but an inoculation eschar is present in only 23% of patients (2). Recently, in a study of 89 FIG 8 Generalized maculopapular rash including face, palms, and soles on a Astrakhan fever patients in Russia, maculopapular rash was de- patient with Mediterranean spotted fever caused by R. conorii subsp. conorii. scribed for 91% of them, solitary elements of which were trans- formed into petechiae in 20% of cases. At convalescence (on day 10.2 Ϯ 1.3 of the disease), all eruptions had regressed, as measured renal failure (245), and the presence of hemophagocytic syn- by pigmentation (256). At the peak of the fever, there were nasal drome (246). In addition to the classical risk factors for malignant hemorrhages and bleeding at the injection sites from medication; MSF (advanced age, immunocompromised situations, chronic al- lowered platelet aggregation was also detected in the presence of coholism, glucose-6-phosphate dehydrogenase [G6PD] defi- thrombocytopenia at the height of the fever (256). To date, no ciency, prior prescription of an inappropriate antibiotic, and delay autochthonous cases have been confirmed in other European of treatment) (209), alcoholism was definitively confirmed as a countries. However, R. conorii subsp. caspia, detected in 9 of 22 risk factor (218), and fluoroquinolone treatment was shown to be ticks in southern France, was associated with a cluster of cases of associated with increased MSF disease severity and longer hospital SFG rickettsioses that were not identified to the species level (254). stays (238). In a study of Italian children, hospitalization was sig- Rickettsia conorii subsp. indica. Rickettsia conorii subsp. indica nificantly longer in the group treated with chloramphenicol than is the agent of Indian tick typhus, prevalent in India and Pakistan. in the group treated with clarithromycin (228). Recently, the mor- R. sanguineus ticks are considered to be the main vectors. In 2012, tality rate in Portugal reached 13% (9/71) of patients with MSF, the first human case in Europe was reported in Sicily by using including many patients with confusion and obtundation (67%), molecular tools for detection (257). This patient had not traveled and a multivariate analysis revealed the following independent but presented with MSF symptoms, with the presence of an inoc- predictors associated with fatal outcome: hyperbilirubinemia, ulation eschar on the right arm. To date, there are no reports of the acute renal failure, and the absence of rash (226). Other fatal cases detection of this bacterium in ticks collected in European coun- were reported in France, Greece, Bulgaria, and Turkey (213, 229, tries. 240, 247). Rickettsia massiliae. The SFG rickettsia R. massiliae was iso- Rickettsia conorii subsp. israelensis. Rickettsia conorii subsp. lated from R. sanguineus ticks collected near Marseille, France, in israelensis is the agent of Israeli spotted fever (ISF), which was first 1992 and then detected in R. sanguineus, Rhipicephalus turanicus, reported in 1946 in Israel (2). R. conorii subsp. israelensis was Rhipicephalus pusillus, Rhipicephalus bursa, and Ixodes ricinus ticks shown to be successfully transmitted transstadially in Rhipicepha- in 8 European countries, including 5 islands: Sardinia and Sicily lus sanguineus from nymphs to adults (38). However, the vertical (Italy), the Canary Islands (Spain), Cephalonia (Greece), and Cy- transmission of this bacterium in its host ticks has not yet been prus (258–263). Dual infections were reported recently in Rhipi- demonstrated. Dogs have been suggested to be a competent res- cephalus ticks: R. massiliae with in Greece and ervoir of R. conorii subsp. israelensis (221, 248). Recently, R. cono- Serbia (264, 265) and R. massiliae with R. conorii subsp. caspia in rii subsp. israelensis DNA was detected in blood samples that were France (254). R. massiliae-infected ticks were collected from ani- recovered from two clinically ill dogs in Portugal within 48 h of mal hosts such as house sparrows, dogs, horses, cats, asymptom- doxycycline administration (209). atic humans (259, 266), hedgehogs (260), red foxes (261), hares, In Europe, R. conorii subsp. israelensis was detected in Rhipi- and goats (258). The reported infection rate of ticks in the wild cephalus sanguineus specimens collected in Sicily and in different ranges from 2% to 92% (254, 260). The introduction of R. regions of Portugal where several clinical cases related to ISF were massiliae to the Canary Islands was suggested to have resulted described (249, 250). The clinical manifestations of ISF are similar from the translocation of infected R. pusillus ticks or from infected to those of MSF. However, a history of tick exposure is reported in wild rabbits migrating from the Iberian Peninsula 600 years ago, 32% of cases, an inoculation eschar is rarely observed (38%), and the latter of which most likely serves as a natural reservoir host for significantly greater gastrointestinal manifestations, such as nau- the pathogen (262). However, no rickettsial DNA was detected in sea (63%) and vomiting (56%), are observed (226). In Portugal, the 150 wild rabbits tested. the 29% case-fatality rate among 69 ISF patients suggests that the In addition to the first Italian human case of R. massiliae infec- ISF strain is more virulent than the Malish strain (226). Other fatal tion (2), a second case was diagnosed by using serological and

676 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World molecular tools in a patient with MSF signs, with complications of acute visual loss and bilateral chorioretinitis. The clinical course was favorable, but 3 months later, the recovery of visual acuity was incomplete (177). The entomological investigation of the house where this patient had been bitten by ticks revealed that 10% of the ticks in the house were infected with a new genotype of R. massiliae. Recently, a Polish study (267) showed the presence of specific SFG rickettsial antibodies in 15% of forest workers; among these workers, 79% had species-specific antibodies to R. massiliae. These results need to be carefully interpreted because current serological tools cannot precisely determine the exact Rickettsia species involved (2). Rickettsia sibirica subsp. mongolitimonae. Rickettsia sibirica subsp. mongolitimonae causes LAR (lymphangitis-associated rick- ettsiosis) and was first isolated in Beijing, People’s Republic of China, from Hyalomma asiaticum ticks collected in Inner Mongo- FIG 9 Enlarged cervical lymph nodes (left) and inoculation eschar of the scalp lia in 1991 (2). In Europe, R. sibirica subsp. mongolitimonae was (right) in a patient with Rickettsia slovaca infection. detected in Hyalomma anatolicum excavatum ticks (5%) in Greece and Cyprus; in R. pusillus ticks (4 to 8%) in France, Portugal, and Spain; and in R. bursa ticks (4%) in Spain (258, 263, 268–270). Human infection with R. slovaca has been described in France, In addition to the LAR cases reported in France and Greece Slovakia, Italy, Germany, Hungary, Spain, and Poland (292, 294). prior to 2005 (2), two autochthonous cases were reported in Por- Infection is most frequent in women (67 to 100%) and children tugal (270, 271), nine were reported in Spain (272–275), and four Ͻ12 years old (41 to 43%). The median incubation period is 5 to were reported in France, including a cluster of three cases in the 10 days (range, 1 to 15 days) (293, 295). The clinical description of same family (268, 276). To date, a total of 24 cases have been R. slovaca infection includes asthenia (70%); headache (53%); reported in four European countries situated in the Mediterra- painful adenopathies (69 to 100%); a painful scalp eschar sur- nean region. Most of the cases reported in France and Spain oc- rounded by a perilesional erythematous halo (64%); and some- curred in the spring (11 cases; 46%) and summer, together with times low fever (36 to 54%), rash (5%), and face edema (291, 292). one from Portugal (9 cases; 38%), likely corresponding to the Antibiotic treatment is successful; however, around the eschar, abundance and activity of these two tick species (277, 278). Inter- alopecia (59%) that lasts for several months as well as prolonged estingly, a history of tick bites was reported in only 41% (7 cases) (35%) or chronic asthenia (14%) often occur (292). To date, pa- of patients. Patients with LAR presented a broad spectrum of clin- tients with R. raoultii infections have been reported in France, ical syndromes with different degrees of severity. No fatal disease Slovakia, and Poland (292, 294, 296), and these patients presented was observed, but complications such as acute renal failure, retinal with clinical signs similar to those listed above, except for alopecia. vasculitis, and lethargy with hyponatriemia have been noted (269, In the Polish case of R. raoultii infection, the multiple dissemi- 275, 276). Typical clinical signs, such as fever (100%), headache nated small lesions had slightly elevated necrotic centers sur- (86%), myalgia (90%), cutaneous rash (77%), enlarged lymph rounded by a red area, whereas the single lesions had a vesicular nodes (71%) and/or lymphangitis (43%), and single or multiple appearance (296). inoculation eschars (92%), in the spring months in the Mediter- Rickettsia monacensis. Rickettsia monacensis was detected in I. ranean area should guide physicians toward accurate diagnoses of ricinus ticks in Spain, Portugal, Italy (including Sardinia), Turkey, this disease. Switzerland, Luxembourg, Germany (including Greifswalder Oie Rickettsia slovaca and Rickettsia raoultii. Rickettsia slovaca Island), Sweden, Slovakia, Albania, Hungary, Bulgaria, Moldova, and Rickettsia raoultii are associated with a syndrome character- Ukraine, Serbia, northwestern Russia (Kaliningrad), Belarus, and ized by scalp eschars and neck lymphadenopathy following tick Poland (208, 280, 283, 289, 297–301). The prevalence of R. mo- bites, and the term “SENLAT” was proposed for this clinical entity nacensis in ticks varied between 1% in Germany, 15% in Serbia, in 2010 (279). Initially, this syndrome was named TIBOLA (tick- 35% Turkey, and 57% in Italy (299, 302). Recently, the DNA of R. borne lymphadenopathy) or DEBONEL (Dermacentor-borne ne- monacensis was detected in lizard tissue (7%) and in their I. ricinus crotic erythema and lymphadenopathy) (Fig. 9). These bacteria ticks (41%) on Madeira Island (Portugal) (303). Those authors have been found in Dermacentor marginatus and Dermacentor re- suggested that lizards may be a potential or transitory reservoir for ticulatus ticks in a great majority of European countries, with a R. monacensis. high percentage of ticks infected with these bacteria (208, 280– In 2005, R. monacensis was identified as a human pathogen in 290). Dermacentor ticks usually bite hairy domestic and wild ani- two patients in Spain (June and September) and in one patient in mals (291). In a recent study in Spain, the seroprevalences of R. Sardinia, Italy (April), by using molecular tools (297, 298). A rick- slovaca in domestic ruminants were reported to be 16% in sheep, ettsial strain was isolated from blood samples of Spanish patients 21% in goats, and 65% in bullfighting cattle. In addition, R. slo- by shell vial culture (298). In addition to fever and flu-like symp- vaca DNA was detected in a goat blood sample, suggesting that R. toms, the inoculation eschar was identified in only one Italian slovaca may be circulating in domestic ruminants (42). patient (left calf), but a generalized rash including the palms and SENLAT occurs most frequently during March to May and soles was identified only in Spanish patients. The patients recov- September to November, which correspond to the periods of ered without sequelae following doxycycline treatment. greatest activity of Dermacentor adult ticks in Europe (292, 293). Rickettsia aeschlimannii. Rickettsia aeschlimannii was detected

October 2013 Volume 26 Number 4 cmr.asm.org 677 Parola et al. in Hyalomma marginatum marginatum and Hyalomma mar- collected from sheep and goats in Croatia, which are closely re- ginatum rufipes ticks in Croatia, Spain, southern France (includ- lated to R. felis (5), and Rickettsia genotype AvBAT from Argas ing Corsica), Portugal, Italy (including Sardinia and Pianosa), vespertilionis, soft bat ticks, collected from southern France (318). Russia, Cyprus, Germany, Turkey, Hungary, and the Greek island In addition, R. hoogstraalii was detected in 30% of the Haemaph- of Cephalonia (258, 299, 304–308). This rickettsia may be spread ysalis punctata ticks collected in Cyprus (258) and in 3% of H. through migratory birds from Africa (308, 309). It was detected in punctata and 16% of H. sulcata ticks from Spain (319). Hyalomma ticks collected from several bird species, such as Acro- cephalus schoenbaenus and Hirondo rustica in Corsica (2) and Lus- Nonvalidated, Incompletely Described, or Uncultivated cinia megarhynchos and Acrocephalus scirpaceus in southern Species France and, in the latter species, in Germany (259, 304). The first human infection caused by R. aeschlimannii was reported for a Fifteen rickettsial genotypes were detected only by molecular tools French patient who became ill after returning from Morocco. This in ticks collected in Europe. “Candidatus Rickettsia tarasevichiae” patient exhibited symptoms similar to those of MSF. To date, no was identified in Ixodes persulcatus ticks with a high prevalence in autochthonous cases of this infection have been reported in Eu- Russia (320). This tick replaces I. ricinus in northern Russia and rope (2). Finland (321). “Candidatus Rickettsia barbariae” was detected in Rickettsia helvetica. R. helvetica is transmitted by I. ricinus,a R. turanicus and R. sanguineus ticks from Portugal, Italy (Sar- sheep tick, which is the main vector and the natural reservoir (2). dinia), France, and Cyprus (258, 259, 306). In a study from Cy- To date, R. helvetica has been detected in I. ricinus ticks in at least prus, a new genotype of “Candidatus Rickettsia barbariae” was 24 European countries. In Denmark, the highest infection rate of designated “Candidatus Rickettsia barbariae” Cretocypriensis R. helvetica in I. ricinus ticks is found in May, followed by July, (258). “Candidatus Rickettsia kulagini” (GenBank accession August, and October (310). In addition, R. helvetica was detected number DQ365806) was detected in R. sanguineus ticks collected in 8% of Ixodes hexagonus ticks, hedgehog ticks, in Germany from the Crimean Peninsula, Ukraine, and a new Rickettsia sp. was (311); in 44% of larvae and 25% of nymphs of I. arboricola that detected in Rhipicephalus turanicus ticks from Cyprus which is were collected from wild birds in the Czech Republic (312); and in closely related to but distinct from the R. rhipicephali-R. massiliae 10% of D. reticulatus ticks in Croatia (287). The DNA of R. hel- lineage (258). “Candidatus Rickettsia siciliensis” was detected in a vetica was detected in hedgehog tissue samples in Germany (311), R. turanicus tick that was removed from an asymptomatic 22- in lizard tissue on Madeira Island (Portugal) (303), and in whole month-old female in Sicily (322). “Candidatus Rickettsia vini” was blood from mice, deer, and wild boar in the Netherlands (311), proposed as a new Rickettsia sp. detected in I. arboricola and I. suggesting that vertebrate hosts play important roles in the geo- ricinus ticks collected from three different bird species in Spain graphical dispersion of rickettsiae. The few patients for whom (317). Rickettsia sp. strain Davousti, previously found in Ambly- serology-based diagnoses exist had relatively mild, self-limited ill- omma tholloni ticks in Africa, was detected in Ixodes species ticks nesses associated with headache and myalgias and less frequently collected from migratory birds in Sweden (323). Furthermore, a with rash and/or an eschar (2). Human infection with R. helvetica sequence with high homology to that of “Rickettsia limoniae” was documented by serology-based diagnoses and sometimes by mo- detected in I. ricinus ticks from the Italian Alpine zone (324). lecular tools was described only in Austria, France, Italy, Den- Rickettsia sp. strain DmS1 was detected in D. marginatus ticks in mark, Switzerland, and Slovakia (2, 294, 313). However, since France and Spain, and 80% of ticks of this species were positive at 2005, no definitive, convincing cases have been published. In par- the fifth generation of a laboratory-maintained infected colony, ticular, recent reports by the same team remain dubious (313– attesting to the tick reservoir in the wild (208, 325). “Candidatus 316). Rickettsia sibirica subsp. sibirica. Rickettsia sibirica subsp. Rickettsia rioja” was detected in D. marginatus ticks collected sibirica, responsible for Siberian tick typhus (STT) in Asia (see from patients with SENLAT syndrome in Spain and France (326, below), was amplified recently in an I. ricinus larva collected from 327). A novel Rickettsia sp. strain (a sister taxon of R. bellii) was Eurasian blackcaps (Sylvia atricapilla) in Spain (317). Those au- detected in I. ricinus ticks collected from common nightingales thors suggested that birds play a significant role in the spread of (Luscinia megarhynchos) in the Czech Republic (328). “Candida- rickettsial agents via infected arthropods. tus Rickettsia kotlanii” was detected in ixodid ticks collected from Hungary (329). “Candidatus Rickettsia moreli” (GenBank acces- Species of Unknown Pathogenicity sion numbers Y08784 and Y08785) was detected in I. ricinus ticks R. rhipicephali was detected and isolated from R. sanguineus ticks from Spain; Rickettsia sp. strain IXLI1, which was detected in I. collected from dogs in 1975 in Mississippi (2). In Europe, this lividus ticks in the United Kingdom, is closely related to R. japon- rickettsia was detected in this tick species collected from France, ica (330); and Rickettsia sp. clone KVH-02-3H7 (GenBank acces- Portugal, Greece (including the Island of Cephalonia), and Croa- sion number GQ849216) was detected in I. ricinus ticks in the tia (2, 264). The intradermal injection of R. rhipicephali in guinea Netherlands. pigs induced the formation of an inoculation eschar at the infec- In the last few years, several pathogenic rickettsial species were tion site, suggesting that this rickettsial species is a potential hu- detected in unusual tick vectors, such as R. australis, R. typhi, R. man pathogen (45). In addition, R. rhipicephali induced mononu- prowazekii, and 4 other uncharacterized Rickettsia spp. related to clear cell inflammation at the site of inoculation, characterized the typhus group in I. ricinus ticks that were collected in the Neth- mainly by macrophages and lymphocytes, similarly to R. conorii erlands (311, 331). Another such example is R. helvetica in D. subsp. conorii. reticulatus ticks in Croatia (287). Thus, interpreting the rickettsial In the last 7 years, two Rickettsia species within the SFG were data is sometimes difficult, and presenting these findings as new or isolated: Rickettsia hoogstraalii from Haemaphysalis sulcata ticks pathogenic rickettsiae should be performed with prudence (332).

678 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 10 Tick-borne rickettsiae in North Africa. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.)

TICK-BORNE RICKETTSIAE IN AFRICA lated from H. marginatum marginatum ticks collected in Morocco North Africa in 1992 (2). The first human infection caused by R. aeschlimannii was in a French patient who became ill after returning from a trip North Africa is defined by the United Nations as the northernmost to Morocco (339). Recently, two new cases were reported in Alge- region of the African continent, including eight countries: Algeria, ria (340). R. aeschlimannii was detected by molecular tools in H. Egypt, Libya, Morocco, South Sudan, Sudan, Tunisia, and West- marginatum marginatum from Algeria (212), Morocco (341), and ern Sahara (Fig. 10). Despite pioneering work conducted in Tuni- Egypt (342, 343). This rickettsia has also been detected in several sia at the beginning of the 20th century, there was an absence of Hyalomma spp., including Hyalomma aegyptium ticks collected rickettsiosis investigations in North Africa after the 1930s (333). However, thanks to clinicians and entomologists in Oran and Al- from Algerian tortoises and Hyalomma dromedarii, Hyalomma giers, respectively, 16 new tick-transmitted rickettsiae have been impeltatum, H. marginatum rufipes, and Hyalomma truncatum described over the last 25 years, including 8 recognized pathogens ticks collected from camels and/or cows in Egypt, Sudan, Algeria, (333). and Tunisia (333). Species identified as pathogens. (i) Rickettsia conorii subsp. (iv) Rickettsia sibirica subsp. mongolitimonae. Two cases of R. conorii. Several case studies of MSF from North Africa have been sibirica subsp. mongolitimonae infection have been reported in published in recent years. In particular, cases have been increas- North Africa, in addition to those reported in Europe. The first ingly reported in Algeria, Tunisia, and Morocco (214, 333). In case reported was an adult female patient who returned to France North Africa, most MSF cases are diagnosed during July and Oc- from a trip to Algeria. She had been in contact with camels, which tober. Although some aspects of MSF were found to align with the are highly parasitized by ticks (344, 345). In September 2009, a general epidemiology of the disease, uncommon aspects were previously healthy 52-year-old man living in France was admitted found, including the increased incidence and the presence of mul- with a 10-day history of fever, asthenia, headache, and arthromy- tiple inoculation eschars in 12% of patients. The role of climatic algia after a 2-week trip to Egypt. He had fever, painful axillary changes in alterations of host-seeking and feeding behaviors of lymphadenopathies, and an inoculation eschar surrounded by an vectors, including R. sanguineus, was discussed (177). Addition- inflammatory halo on the left scapular area, but he did not have a ally, in Algerian cases, 49% of patients were hospitalized with a rash. During his travel, he had been unsuccessfully treated for severe form of the disease. The overall case-fatality rate was 3.6%, headache, arthromyalgia, and diarrhea by amoxicillin-clavu- but it was 54.5% for patients hospitalized with major neurological lanate, nonsteroidal anti-inflammatory drugs, and gentamicin manifestations and multiorgan involvement (334, 335). In addi- cream on the eschar for 3 days. He improved and remained well tion, direct contact with dogs or domestic animals has been re- after doxycycline treatment (344, 345). ported in 76.5% to 95.2% of the cases, and a history of a tick bite (v) Rickettsia slovaca and Rickettsia raoultii. R. slovaca and R. has been found in 38% to 50.3% of the cases (333). R. conorii raoultii, agents of TIBOLA/SENLAT (see the section on Europe subsp. conorii was detected by molecular tools in R. sanguineus above), were detected in D. marginatus ticks in 2008 in Morocco ticks from Algeria (212), Tunisia (336), and Morocco (337). (341) and recently in D. marginatus tick species collected in north- (ii) Rickettsia conorii subsp. israelensis. The agent of the so- ern Algeria (346). However, no human case has been reported in called ISF has been found in Sfax (southern Tunisia). Physicians northern Algeria. took note of patients with severe forms of MSF and suspected the (vi) Rickettsia monacensis. After the first two human cases of presence of other species or a virulent R. conorii strain. Two cases infection due to R. monacensis documented in Spain (208), R. of ISF that were reported from Sfax were confirmed by the detec- monacensis was detected in I. ricinus ticks in Morocco (341), in tion of rickettsial DNA in skin biopsy specimens (338). Tunisia (347), and twice in Algeria (346, 348). In Algeria, R. mo- (iii) Rickettsia aeschlimannii. R. aeschlimannii was first iso- nacensis was detected in ticks collected in the far-eastern region of

October 2013 Volume 26 Number 4 cmr.asm.org 679 Parola et al.

FIG 11 Tick-borne rickettsiae in sub-Saharan Africa. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathoge- nicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.)

Algeria (Tarf) (348) and in the central region (Tizi Ouzou) in 2010 (2). In 2009, the transovarial transmission rate of R. africae in the (346). No human case has been reported in northern Africa. third generation of naturally infected A. variegatum ticks was es- (vii) Rickettsia massiliae. R. massiliae (see sections on Europe timated to be 100%, and the filial infection rate (the proportion of and South America above) has been found in ticks in North Africa. infected eggs or larvae obtained from an infected female) was es- It was isolated from R. turanicus and Rhipicephalus sanguineus timated to be 93% (30). The infection rate in these tick species in ticks in Algeria (212), and it has been detected in R. sanguineus and regions of endemicity is high and may reach 100% (13, 351), R. bursa ticks in Morocco (337, 341). However, no human case has which suggests an extreme fitness of this rickettsia for its vector been reported in northern Algeria. (13). Since 2005, R. africae has also been detected in Amblyomma (viii) Rickettsia africae. R. africae, the agent of African tick bite lepidum ticks (20%) in Djibouti (352); Rhipicephalus annulatus fever (ATBF), has very recently been detected in North Africa, ticks (2 to 93%) in Guinea, Senegal, and Nigeria (41, 351, 353); including in H. dromedarii ticks collected from camels (Camelus Rhipicephalus evertsi evertsi ticks (0.4 to 5%) in Senegal and Nige- dromedarius) in Algeria and in Egypt (342, 343). The role of H. ria (41, 353); Rhipicephalus decoloratus ticks (5 to 77%) in Nigeria dromedarii in the epidemiology of R. africae requires further in- and Botswana (354, 355); Rhipicephalus sanguineus (5%) and Hy- vestigation. However, no human case of ATBF has been reported alomma impeltatum (10%) ticks in Nigeria (354); Rhipicephalus in northern Algeria. geigyi ticks (14%) in Liberia (356); and Amblyomma compressum (ix) Rickettsia helvetica. R. helvetica is prevalent in Europe (see ticks (10 to 50%) in the Democratic Republic of the Congo and above). A small population of I. ricinus ticks is present in Tunisia, Liberia (356, 357). However, their role in the epidemiology of Algeria, and Morocco. R. helvetica is also present in North African ATBF is unknown, as the rate of infection in Rhipicephalus ticks is countries, including Morocco (341), Tunisia (347), and, very re- always lower and may be considered concomitant, acquired most cently, Algeria (346). likely by cofeeding (356) or via a bacteremic animal (355). To Nonvalidated, incompletely described, or uncultivated spe- cies. A Rickettsia sp. from the SFG was detected in Rhipicephalus date, R. africae has been detected in ticks and/or humans in 22 sanguineus and Haemaphysalis erinacei ticks collected from hedge- sub-Saharan African countries (Fig. 11). hogs in Algeria (349) and in Haemaphysalis ticks from Morocco A high R. africae seropositivity rate was detected in indigenous (341). This Rickettsia species is phylogenetically close to R. hei- populations in rural areas. For example, the seropositivity rates in longjiangensis. Cameroon and Senegal were 12 to 52% (358) and 20.6 to 45.6%, respectively (353). The highest seroprevalence in Cameroon was Sub-Saharan Africa linked to the presence of cattle, the preferred host of A. variega- Species identified as pathogens. (i) Rickettsia africae. R. africae tum, and with lowland rainforest habitats, ideal for the behavior of causes ATBF (2). In southeastern Africa, A. hebraeum, known as this tick species (358). However, since 2005 (2), more than 141 the South African bont tick, is a recognized vector and reservoir acute ATBF cases were reported in international travelers (359– for R. africae. Elsewhere in sub-Saharan Africa, A. variegatum 385), but none were reported from native populations. In addition, (350), the tropical bont tick, is a documented vector of R. africae 197 spotted fever cases, most likely ATBF, in travelers from sub-Sa-

680 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

Republic and has been isolated from Haemaphysalis leachi and Rhipicephalus simus ticks from dogs in Zimbabwe. All of these ticks are suspected to be potential vectors in sub-Saharan Africa (2). Recently, R. conorii was detected in a Rhipicephalus evertsi evertsi tick (1/268) collected from a horse in rural Senegal (353) and in a Haemaphysalis punctaleachi ticks (1/9) from a dog in Uganda (352). These ticks seldom feed on humans, and their role as vectors of R. conorii subsp. conorii in these areas has not been demonstrated. R. conorii DNA was detected in a blood sample collected from a febrile 4-year-old girl with tachycardia, who was among 134 other febrile patients from Sine-Saloum, Senegal, who were ana- lyzed (353). This patient recovered without antibiotics (353), but another MSF case mimicking a hemorrhagic viral fever had a fatal FIG 12 Eschar in a patient with African tick bite fever caused by R. africae. outcome for a South African man (390). In all these cases (353, 390, 391), the lack of a tick exposure report and the lack of patho- gnomonic signs such as an inoculation eschar or skin rash have haran Africa have been reported by the GeoSentinel network during contributed to the lack of any clinical suspicion. This absence of June 1996 to December 2008. In 2006, 30 GeoSentinel sites, which suspicion potentially led to the delayed introduction of a specific are specialized travel or tropical medicine clinics on six conti- antimicrobial therapy. In MSF, the absence of an inoculation es- nents, compared the frequencies of the occurrence of each diag- char has been described in 14 to 40% of MSF cases (215), and the nosis among travelers (118). ATBF was the second most fre- absence of maculopapular rash has been described in 1 to 4% of quently identified etiology, after malaria, among travelers cases (226). However, this rash may be imperceptible in patients returning from sub-Saharan Africa (118). This finding was con- with pigmented skin (215). Seven more benign MSF cases were firmed subsequently by other studies (383, 386). The risk factors reported in international travelers from sub-Saharan Africa, in- for ATBF in travel are male gender, higher age, travel for tourism, cluding one from South Africa, one from Swaziland, and one from and travel during the late summer months in southern Africa Kenya (373, 383, 392, 393). As MSF and ATBF are the most en- (March to May) (385, 387). demic rickettsioses in these areas, clinicians are encouraged to Actually, the diagnosis of ATBF, which remained unrecog- contact a specialized laboratory to better identify the rickettsial nized for years, is usually based on travel history and clinical pre- agent. sentation with flu-like symptoms associated with one or multiple (iii) Rickettsia conorii subsp. caspia. Rickettsia conorii subsp. inoculation eschars (Fig. 12) and grouped cases (attack rate, 33 to caspia is the agent of Astrakhan fever. Since the isolation of this 100%), which is explained by the hunting strategy of tick vectors. bacterium from a patient returning from Chad with fever and a Ticks attack hosts, emerge from their habitat, and run toward their maculopapulous rash (2), no other reports of isolation in humans hosts when these animals appear nearby (367, 379). Recently, or ticks were reported from sub-Saharan Africa. more than 100 A. hebraeum ticks were identified on the extremi- (iv) Rickettsia aeschlimannii. R. aeschlimannii caused a spot- ties and trunk of one Japanese woman with a confirmed ATBF ted fever in one case in South Africa after a Rhipicephalus appen- diagnosis after she traveled to South Africa (374). The rash is ob- diculatus tick bite (2). However, Hyalomma ticks seem to be the served in 30 to 88% of patients and is mostly maculo- or papulo- main vectors and reservoirs of R. aeschlimannii. Recently, it was vesicular (364, 367, 373). ATBF is a benign disease; nevertheless, a detected in 45 to 51% of H. marginatum rufipes specimens and 6 to more severe course was described in elderly populations (364, 7% of H. truncatum specimens collected from cows, donkeys, 365), and some complications, such as subacute cranial or periph- sheep, goats, and horses in Senegal (353). In addition, one R. ae- eral neuropathy and chronic fatigue (364, 388), internuclear oph- schlimannii strain, RH15, was isolated from an H. truncatum spec- thalmoplegia (381), myocarditis (364, 376), and cellulitis, have imen collected in Senegal (353). H. marginatum rufipes is widely been reported (365). One coinfection with Leishmania tropica was distributed in much of Africa, commonly in the drier areas, and reported after travel to Botswana (389), and one with Coxiella the infestation of birds by the immature stages of this tick contrib- burnetii, the agent of , was reported after a trip to the utes to its extensive distribution and the spread of infected ticks. Gambia (375). Recently, comparative genome analysis may have Unexpectedly, R. aeschlimannii was detected in 0.7 to 5% of the explained the low virulence level of R. africae in humans and its R. evertsi evertsi specimens from Senegal and Nigeria (41, 353) and strong adaptation to its tick host. In fact, R. africae had 18 fully in 2% of the R. annulatus specimens and 2% of the A. variegatum conserved genes that were either absent or degraded in other spe- specimens from Nigeria (41). In one Nigerian study (41), it was cies, such as R. prowazekii, R. rickettsii,orR. conorii (13). In addi- detected only in feeding ticks, suggesting that cattle may play a role tion, analysis of 102 human and tick strains suggested that R. as an animal reservoir. To date, this bacterium has been detected africae is clonal, a unique characteristic among the SFG rickettsia in 8 sub-Saharan African countries. species (13). (v) Rickettsia sibirica subsp. mongolitimonae. R. sibirica (ii) Rickettsia conorii subsp. conorii. Rickettsia conorii subsp. subsp. mongolitimonae, the agent of LAR, was described in a fe- conorii, the agent of MSF, has been reported in 9 sub-Saharan brile man from South Africa with a toe eschar and lymphangitis African countries to date (Fig. 11). Although the recognized vector (2). Recently, in Senegal, R. sibirica subsp. mongolitimonae was of R. conorii is R. sanguineus, this rickettsia has been detected in detected in 14% of H. truncatum ticks, with the isolation of one Rhipicephalus mushamae ticks from cattle in the Central African strain, RH05, in cell culture (353). The infected H. truncatum ticks

October 2013 Volume 26 Number 4 cmr.asm.org 681 Parola et al. were collected from cattle, donkeys, sheep, goats, and horses spite of some clinical and epidemiological differences, the distinc- (353). H. truncatum ticks are common in sub-Saharan Africa, and tion between these two rickettsiae is possible only by molecular their abundance is influenced by the hare population, the host methods. The incidence of STT in Russia is continuously increas- during the immature stages. As immature ticks can attach to hu- ing, varying between 2.5 and 4.0 per thousand officially registered mans, LAR is most likely distributed across almost all of these cases per year (400) and reaching 50 to 55 per thousand in regions countries. of endemicity, especially Altay and Krasnoyarsk (2, 401). It is most (vi) Rickettsia massiliae. R. massiliae is a pathogenic rickettsia likely the most prevalent rickettsiosis in Asia. that is epidemiologically associated with the hard ticks of the ge- The most important vectors are Dermacentor ticks; however, nus Rhipicephalus. It was described as a human pathogen in Eu- Haemaphysalis and even Ixodes ticks have also been implicated rope and South America (see above), but there has been no report (402). The infection rate in Dermacentor ticks may vary from 8.3 from Africa. However, a high infection rate was detected in Rhi- to 13.0% (403, 404). The morbidity is strongly seasonal, with picephalus guilhoni ticks (22%) that were collected from donkeys peaks in April and May (120), corresponding to the peaks in ac- and cows in Senegal (353) and in Rhipicephalus senegalensis ticks tivity of Dermacentor ticks in Siberia. Children younger than 14 (8%) in Guinea (356). Recently, R. massiliae was detected while years of age comprise up to 75% of patients (399). searching for R. evertsi ticks (3%) collected from the vegetation at The mean incubation period is 4 days, and the clinical features seven Nigerian locations by cloth dragging and by direct hand are typical for a spotted fever, including a high fever associated picking, suggesting that these bacteria are surviving and easily with an inoculation eschar that is often accompanied by regional being perpetuated in the wild (41). In addition, the R. massiliae lymphadenopathy and a maculopapular (rarely with a hemor- Guinean genotype was detected by molecular tools in 16% of Rh- rhagic component) rash. This disease is usually mild and is seldom ipicephalus senegalensis and in 2% of Haemaphysalis paraleachi associated with severe complications (2). ticks collected from dogs in Guinea (356). Rickettsia heilongjiangensis. The first cases of FESF caused by Species of unknown pathogenicity. Two rickettsial species of R. heilongjiangensis, exhibiting mild rash associated with fever and unknown pathogenicity were detected in ticks in sub-Saharan Af- an eschar, have been reported in the Russian Far East and the rica. R. rhipicephali was detected for the first time in the Central People’s Republic of China (2). In both countries, FESF cases were African Republic in 1994 in Rhipicephalus lunulatus and Rhipi- most likely misdiagnosed as STT before molecular tools became cephalus composites group ticks (2). Since then, it has not been available (120, 399). Recently, the first case from Japan was also detected in ticks in these geographical areas. In 2012, R. hoogstraa- reported (405). In Russia and China, R. heilongjiangensis was iso- lii was detected in Argas persicus ticks from Ethiopia (394). lated from Haemaphysalis concinna and Dermacentor silvarum Nonvalidated, incompletely described, or uncultivated spe- ticks (402, 406). The rate of infection in H. concinna ticks may cies. “Candidatus Rickettsia liberiensis,” which is genetically close reach up to 28% (406). R. heilongjiangensis was also identified in to R. raoultii, was detected in Ixodes muniensis ticks collected from Haemaphysalis flava ticks (407) in central China. Wild animals, dogs in Liberia (356). In Gabon, Rickettsia sp. strain Davousti, usually Rattus edwardsii, Rattus fulvescens, Rattus nivivente, Rattus which is phylogenetically close to R. heilongjiangensis, and in the flavipectus, and Berylmys bowersi, are considered reservoirs for this Central African Republic, Rickettsia sp. strain Uilenbergi, which is bacterium in nature (408). However, recently, the DNA of this phylogenetically close to the R. massiliae group, were detected in rickettsia was identified in the blood of goats in China (409). Amblyomma tholloni ticks, both of which were collected from el- It was recently shown that, compared to STT, the peak of mor- ephants (395). A. tholloni ticks rarely feed on humans and occur bidity of FESF in the Russian Far East is much later, in July. This widely in Africa, following the distribution of the African ele- peak corresponds to the month exhibiting the highest level of phant: from South Africa in the south to the Sudan in the north activity of Haemaphysalis ticks. Moreover, the affected population and from Sierra Leone in the west to Somalia in the east. In addi- is much older, especially the 50-and-older age group (399, 406). tion, one Rickettsia species belonging to the R. rickettsii group was The pathogenicity of R. heilongjiangensis was not studied until detected in R. evertsi ticks in Nigeria (41), and another rickettsial recently, when the pathological inflammatory effects were de- species (GenBank accession numbers DQ092217 and DQ092215) scribed in a mouse model (410). that is closely related to R. felis based on their 17-kDa antigen The distribution of R. heilongjiangensis is most likely much sequences and is closely related to Rickettsia cooleyi based on their larger than the Russian Far East and northern China, as a phylo- citrate synthase genes was detected in Ornithodoros moubata,a genetically related strain, PMK94, was isolated from a patient with soft tick from Tanzania (396). septic shock in Thailand (411, 412). Rickettsia japonica. R. japonica is the etiological agent of Jap- TICK-BORNE RICKETTSIAE IN ASIA anese spotted fever (JSF), the typical spotted fever identified in southwestern Japan. It is characterized by fever, headache, and the Species Identified as Pathogens appearance of an eschar and a rash (413). The main vectors are H. Rickettsia sibirica subsp. sibirica. Siberian tick typhus (STT), flava, Haemaphysalis hystricis, Haemaphysalis longicornis, Haema- caused by R. sibirica subsp. sibirica, was described in Russia in the physalis cornigera, Haemaphysalis formosensis, Ixodes ovatus, and 1930s (2). Since then, STT has been found across a large territory Dermacentor taiwanensis (2, 414). The reservoirs may be wild ro- from the Pacific coast to western Siberia in Russia, China, Mon- dents and small carnivores such as feral raccoons (415). Until golia, and Kazakhstan (120, 397)(Fig. 13). Recent studies describe recently, JSF was thought to be restricted to Japan. Recently, how- several serologically confirmed cases from South Korea (398). At ever, a large amount of data to the contrary have become available. least some of the STT cases reported previously in the Russian Far Closely related Rickettsia spp. were detected in H. longicornis ticks East were most likely misdiagnosed Far-Eastern spotted fever by PCR in South Korea (416). In northern Thailand (Chiang Mai), (FESF) caused by Rickettsia heilongjiangensis (see below) (399). In strain TCM1 was isolated from H. hystricis ticks; phylogenetic

682 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 13 Tick-borne rickettsiae in Asia. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.) analysis showed that it is most closely related to Japanese strains israelensis was first isolated in 1974 in Israel, and its genome was (412). The complete genome of this rickettsia was recently pub- recently sequenced (2, 426). It is the agent of ISF (2). Like MSF, ISF lished (417). is transmitted by infected R. sanguineus ticks. Human cases of Rickettsia sibirica subsp. mongolitimonae. First described in spotted fever have been reported since the late 1940s in Israel; Inner Mongolia, China, Rickettsia sibirica subsp. mongolitimonae however, recently, disease caused by R. conorii subsp. israelensis is widely distributed in Hyalomma ticks in Southern Europe and was reported in Italy, Portugal, and Tunisia (253, 426). The eschar Africa (418). The presence of the DNA of this rickettsia in Hya- at the inoculation site typical of MSF is usually lacking. lomma sp. ticks from Israel was also reported (419). Despite a Rickettsia honei. R. honei is another SFG rickettsia that was number of human cases reported in Europe and Africa (see described as a new species in 1998 and as the cause of Flinders above), no report of morbidity from Asia is currently available. Island spotted fever (FISF) in Australia (427). The original Thai Rickettsia conorii subsp. conorii. The only place in Asia in tick typhus isolate, TT-118, was obtained from a mixed pool of which MSF was reported is a Bursa province in Turkey (236). The Ixodes sp. and Rhipicephalus sp. larval ticks from Rattus rattus disease is transmitted by brown dog ticks, R. sanguineus (2); how- trapped in Chiangmai Province, Thailand, in 1962 and has re- ever, other species, such as R. bursa, may also be implicated (299). cently been determined to be a strain of R. honei (428). This dis- Rickettsia conorii subsp. indica. R. conorii subsp. indica is the covery significantly enlarged the geographical distribution of this agent of Indian tick typhus, a tick-borne rickettsiosis prevalent in pathogenic rickettsia. The first molecularly confirmed case in India (420, 421), with solitary cases reported from Laos (422) and Thailand was reported in 2005 (428); however, many serologically Sri Lanka (423). Clinically, the disease resembles MSF; however, a verified spotted fever cases have been reported in Thailand (429). series of three severe cases complicated by gangrene were reported Recently, a severe case of tick-borne rickettsiosis caused by R. recently (424). It was isolated in 1950 from R. sanguineus ticks honei was reported in Nepal (430). The typical clinical picture of collected in that country, although it has never been isolated in spotted fever was associated with encephalitis, pneumonitis, tin- patients there (2). Indian tick typhus also differs from MSF, the nitus, and deafness. The complete genome of the RB(T) strain of disease caused by the R. conorii strain type, in that the rash is often R. honei was recently sequenced and published (431). purpuric, and an inoculation eschar at the bite site is seldom iden- Rickettsia tamurae. R. tamurae was isolated from Amblyomma tified (425). The genome of R. conorii subsp. indica was recently testudinarium ticks in Japan (7). The typical hosts of this tick are published (425). wild and domestic pigs, but the tick also infests deer, cattle, other Rickettsia conorii subsp. israelensis. Rickettsia conorii subsp. livestock, and humans. Wild boars in Japan may be infected by R.

October 2013 Volume 26 Number 4 cmr.asm.org 683 Parola et al. tamurae, which is found in skin biopsy specimens and ticks (432). Rickettsia africae. R. africae, the agent of ATBF, is usually as- Until recently, it was not thought to be pathogenic, but the first sociated with Amblyomma ticks. However, it has been detected in human case was reported in 2011 in Japan (433). However, a spot- several species of Hyalomma ticks, including H. dromedarii in ted fever case reported from Laos was seroreactive for the R. ta- Egypt (342). Similarly, R. africae was reported in H. aegyptium murae antigen (422). ticks from Turkey (299). No human cases from Asia have been “Candidatus Rickettsia kellyi.” “Candidatus Rickettsia kellyi” reported to date. is phylogenetically very distant from all known species to date. No isolates exist; however, the ompA gene of this rickettsia was Species of Unknown Pathogenicity sequenced from the skin biopsy specimen of a 1-year-old child Rickettsia asiatica was isolated from I. ovatus ticks in Japan (3). with clinical signs of spotted fever in India (434). Several closely Some closely related species were also reported in China and related sequences (GenBank accession numbers HM587248 to South Korea in I. ovatus and I. pomerantzevi ticks (GenBank ac- HM587251) without a supporting published manuscript were re- cession numbers AB297812 and AB297808). Up to 63% of wild cently deposited in GenBank; they were also amplified from skin sika deer may have the DNA of this rickettsia in their blood, indi- biopsy samples of Indian patients. cating that they could be a potential reservoir (440). Rickettsia aeschlimannii. No cases of R. aeschlimannii infec- tion in Asia have yet been reported. This species is thought to be Nonvalidated, Incompletely Described, or Uncultivated associated mostly with Hyalomma species ticks in Africa, Europe, Species and Asia, where it was identified in H. punctata ticks in Kazakh- Three strains of rickettsia closely related to R. rhipicephali were stan (120) and H. sulcata ticks in Georgia (290). It was also de- isolated from Rhipicephalus haemaphysaloides ticks in Taiwan tected in Hyalomma marginatum and Hyalomma detritum ticks in (441). “Candidatus Rickettsia tarasevichiae” was identified in I. Israel (435). persulcatus ticks almost everywhere in Asiatic Russia (2, 406). It Rickettsia raoultii. R. raoultii was described as a new species in was also identified in I. persulcatus ticks in Hokkaido (438). The 2008 (292). The type strain, Kharbarovsk, was isolated from D. pathogenicity of this rickettsia for humans is not yet known. A silvarum ticks in the Russian Far East (6). Since then, this rickettsia strain that has yet to be named, IG-1, was isolated from Ixodes has been identified in different parts of Asiatic Russia (Omsk, granulatus ticks from Taiwan. Phylogenetic analysis showed that Novosibirsk, and Buryatiaya) and Kazakhstan in different species this strain may belong to a new species (442). Identical rickettsiae of Dermacentor ticks, including D. reticulatus, D. marginatus, and were later found in I. granulatus ticks in Japan (443). R. hoogstraa- D. nuttalli. The most recent report also shows that this rickettsia is lii was originally isolated in 2006 from H. sulcata ticks from Cro- widely distributed in northern China (436) and Mongolia (404). atia and Carios capensis ticks from the United States (5). However, Similar rickettsiae were also identified in D. niveus ticks in China a detailed search showed that in 2006, this rickettsia was already (GenBank accession numbers JQ664721 and JQ664722); H. hys- identified in C. capensis soft ticks in Japan (444). “Candidatus tricis ticks in Japan (accession number JQ697956); and Haemaph- Rickettsia principis” was identified in 1.5% of Haemaphysalis ja- ysalis ornithophila, Haemaphysalis shimoga, Haemaphysalis la- ponica douglasi ticks from the Russian Far East (406). A closely grangei, and A. testudinarium ticks in Thailand (437). It was also related species was soon identified in Haemaphysalis danieli ticks detected in D. marginatus ticks in Turkey (299) and Georgia (290). recovered from cattle in the Xinjiang Uygur Autonomous Region No cases from Asia have been reported to date. Area, China (445). Rickettsia slovaca. R. slovaca is responsible for at least two- thirds of all TIBOLA cases in Europe (see above) (292). The geo- TICK-BORNE RICKETTSIAE IN AUSTRALIA AND THE PACIFIC graphical distribution of R. slovaca and R. raoultii most likely cor- In the Oceanic region, there are a number of recognized tick- responds to the geographical distribution of Palearctic transmitted SFG rickettsiae, but they are limited mostly to Austra- Dermacentor spp.: R. slovaca was also found in D. marginatus ticks lia (Fig. 14). Investigation of the presence of rickettsiae in regions in the Kurgan region (Ural) of Russia (402) and in Georgia (290) outside Australia has just started, and anecdotal evidence suggests and in 6.5% of D. silvarum ticks in China (436). Human cases have that SFG rickettsioses are underreported and more widespread not been reported in Asia. than is currently known. Tick-borne SFG rickettsiae have yet to be Rickettsia helvetica. In Asia, R. helvetica was identified in Ixodes reported from New Zealand or any of the 20 other major Pacific persulcatus ticks in Hokkaido, Japan (438), as well as in Ixodes Island nations; however, further research is required to verify their ovatus and Ixodes monospinosus ticks (2). It was also reported in presence or absence from these regions. Turkey, where the distribution area of I. ricinus ticks touches Asia. Serologically confirmed human cases were reported from Laos Species Identified as Pathogens (422) and Thailand (2). DNA of R. helvetica was also identified in Rickettsia australis. The first cases of tick-borne rickettsiosis in the blood of wild feral raccoons (Procyon lotor) in Japan (415). Australia were reported in 1946 from Queensland, with two iso- Rickettsia massiliae. R. massiliae has been regularly identified lates from the reported cases (2). Caused by tick bites and with a in R. turanicus and R. sanguineus ticks all over their distribution clinical presentation similar to that of , the disease areas, including Israel (419, 435). Additionally, both Rhipicepha- was named Queensland tick typhus (QTT). Serological analysis of lus species are widely distributed in Middle and Central Asia isolates demonstrated its uniqueness relative to other known rick- (439). The distribution area of R. massiliae may also include these ettsiae, which led to it being named R. australis. The three tick regions; however, no recent reports from these regions are avail- species that have been identified as vectors of R. australis are Ixodes able. tasmani, Ixodes holocyclus, and . The distributions Rickettsia monacensis. R. monacensis, recently considered of the ticks that have been found to harbor R. australis are located pathogenic, was identified in I. ricinus ticks in Turkey (299). along the eastern states ranging from the Torres Strait islands to

684 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

FIG 14 Tick-borne rickettsiae in Australia. Colored symbols indicate pathogenic rickettsiae. White symbols indicate rickettsiae of possible pathogenicity and rickettsiae of unknown pathogenicity. (Adapted from reference 2.) northern Queensland through to Wilsons Promontory, Victoria subsequently described in Thailand (428) and, most recently, Ne- (446, 447). pal (430). The tick vector for R. honei in Australia is Bothriocroton Symptoms associated with QTT include headache, chills, mal- hydrosauri, previously known as Aponomma hydrosauri (451). aise, fever, maculopapular rash (Fig. 15), and an eschar that is Geographically, human cases of FISF and ticks harboring R. honei found at the tick bite site. Cases of R. australis infection are seldom have thus far been limited to the states of South Australia and reported in the literature but do occur, with the severity of disease Tasmania (452–454). However, B. hydrosauri has been observed ranging from very mild to life threatening. Fatalities linked to R. in other states, including Victoria and New South Wales; no evi- australis infection are rare, and severe disease in patients with dence of R. honei has been reported from these areas. underlying problems is uncommon (448–450). Rickettsia honei strain marmionii. The rickettsia described by Rickettsia honei. The first cases of R. honei infections were re- Lane et al. (455) was most likely the first description of Rickettsia ported by Stewart in 1991, and the rickettsia-like symptoms were honei strain “marmionii” in Australia. This strain is similar to R. initially mistakenly attributed to R. australis (2). The compara- honei, with some slight genetic variations that are not distinct tively different clinical presentation (the rash was maculopapular, enough to warrant classification as a new species. Due to its ex- and there was no vesiculation), seasonality (December through panded geographic range in four states (South Australia, Victoria, January instead of June through November), and geographical Tasmania, and Queensland) and its different tick hosts, recogni- location compared to that of QTT warranted the newly discovered tion was given to its uniqueness from R. honei (456). The Haema- rickettsial disease to be named FISF. The rickettsiosis is generally physalis novaeguineae ticks that harbor R. honei strain marmionii mild, with symptoms such as fever, myalgia, headache, cough, and typically infest macropods and are prevalent in northern Australia rash (2). Although R. honei was first discovered in Australia, it was and Papua New Guinea. The tick vectors responsible for the trans- mission of R. honei strain marmionii in the southern states are unknown. It has been detected in infected patients only by molec- ular techniques (456, 457). The rickettsiosis caused by R. honei strain marmionii has a clinical presentation similar to that of FISF, with fever, headache, arthralgia, myalgia, cough, maculopapular/ petechial rash, nausea, pharyngitis, lymphadenopathy, and eschar (456). However, given the large geographical distribution of this agent, the disease would be more appropriately described as Aus- tralian spotted fever. Rickettsia africae. Cases of R. africae in Australia and the oce- anic region are commonly reported in travelers returning from sub-Saharan Africa (458). However, a recent report of R. africae in Amblyomma loculosum ticks in New Caledonia provides evidence that the geographic endemicity of this organism goes well beyond its traditional location in continental Africa (459). A. loculosum is endemic to the islands in the Indian Ocean and South Pacific and has been found on various vertebrates, including marine birds, local mammals, and reptiles (452). It is believed that R. africae may have been introduced to New Caledonia by migrating birds rather than with the importation of cattle, as was the case in the West FIG 15 Maculopapular rash on the legs of a patient with Queensland tick Indies (2). Although there are no reports of rickettsiosis transmit- typhus caused by Rickettsia australis. ted by tick bites or linked to locally acquired African tick typhus in

October 2013 Volume 26 Number 4 cmr.asm.org 685 Parola et al.

Australia or New Caledonia, the presence of the disease cannot be Serological tests are still the easiest, most frequently used, and excluded. most widely available method for the diagnosis of rickettsiosis. However, even when using the immunofluorescence reference Species of Unknown Pathogenicity method, seroconversion is usually detected 7 to 15 days after the Rickettsia gravesii. Evidence of SFG rickettsiosis in Western Aus- onset of disease (25 to 28 days for R. africae infection). Most com- tralia has been established for several years with the use of sero- mercially available MIF assays and even national reference centers logical assays; however, no rickettsial agents have ever been char- offer a very limited selection of antigens that cross-react with dif- acterized in human specimens. The clinical presentation of this ferent rickettsiae. disease must be relatively mild, as it is generally not detected. In this context, it is important for practicing physicians to re- Rickettsia gravesii is a recently described species with a close geno- member that MIF may be adequate for diagnosis of spotted fever typic association with R. raoultii and R. aeschlimannii but distinct rickettsiosis but that it is likely to be insufficient for definitive enough to warrant its acceptance as a novel rickettsial species (460, identification of the etiologic agent. More sophisticated serologic 461). It has been found to be highly prevalent among tick popu- assays, such as cross-absorption (CA) techniques and Western lations in Western Australia. The prevalence has been shown to be blotting (WB), can be used to help to differentiate rickettsial in- Ͼ70% in Amblyomma triguttatum ticks (462), which are widely fections by antibody evaluation, but these methods are only now known to bite large vertebrate mammals, including humans becoming available at the WHO collaborative center in Marseille, (463). These ticks are found in all states and territories of Australia France. and are aggressive feeders, which implies that R. gravesii has a In cell culture, rickettsiae may be detectable as early as 48 to 72 potential vector that can transmit this agent across Australia. h postinoculation. Additionally, the isolation of Rickettsia species Rickettsia argasii. “R. argasii” (GenBank accession numbers from samples using cell culture, particularly the shell vial tech- JQ727682 and JQ727683) was recently isolated from the soft tick nique, remains critical for the description of new species, enabling Argas dewae from bat roosting boxes in Victoria, Australia. These genetic descriptions, physiological analyses, improvement of di- ticks are found primarily on the microbats Chalinolobus gouldii agnostic tools, and antibiotic susceptibility testing of bacteria. Al- and Vespadelus sp. The potential for geographical spread of this though the development of cell culture systems for viral isolation agent is high, as bats are known to travel great distances. No rick- has led to an increase in the number of laboratories suitably ettsiosis has so far been attributed to R. argasii, nor has the rick- equipped to isolate rickettsiae, the isolation of rickettsial organ- ettsia been found in other tick species. The potential for human isms remains difficult, and few reference centers are able to do so. rickettsiosis is believed to be extremely low due to the host-specific To be suitable for culture, samples must be collected prior to the nature of this tick. initiation of an antibiotic regimen and as early as possible in the course of the disease. Nonvalidated, Incompletely Described, or Uncultivated To reduce the delay in diagnosis, molecular tools for the diag- Species nosis of human rickettsiosis allow both convenient and rapid de- Six other rickettsiae determined to be highly divergent from other tection and identification of rickettsiae. known rickettsiae worldwide have been mentioned in the litera- Although culture is less sensitive than serology and quantita- ture; however, culture isolation has thus far been unsuccessful. tive PCR (qPCR) for the diagnosis of tick-borne rickettsiosis, it These six rickettsiae have been tentatively named “Rickettsia an- has recently been shown that skin biopsy specimens (from rash techini” (detected in Ixodes antechini)(427), “Rickettsia derrickii” and/or eschar) cultivated in a reference center can be positive even (in Bothriocroton hydrosauri)(427), “Rickettsia guntherii” (in when molecular tests are negative and that a negative result by the Haemaphysalis humerosa)(427), “Rickettsia sauri” (in Bothriocro- use of molecular assays does not exclude the diagnosis of rickett- ton hydrosauri)(427), “Rickettsia tasmanensis” (in Ixodes tas- siosis. A positive correlation between the bacterial copies and iso- mani)(464), and koala rickettsia (in Bothriocroton concolor)(427, lation success in skin biopsy specimens and ticks was also found. 465). Their pathogenic potential is unknown, their presence in To increase the sensitivity of the culture, skin biopsy specimens ticks was detected by PCR assays, and their novelty was deter- should be sampled before treatment and early in the course of the mined by genotypic analysis of PCR amplicons. disease and should be inoculated as soon as possible (466). A new step for the diagnosis of tick-borne rickettsioses has NEW APPROACHES TO DIAGNOSIS been achieved recently with the emergence of the use of quantita- Generally, the clinical symptoms of tick-borne SFG rickettsioses tive real-time PCR (467–469). Genomic approaches have recently begin 4 to 10 days after a bite and typically include fever, headache, increased our knowledge of the genus Rickettsia, and massive muscle pain, rash, local lymphadenopathy, and, for most of these amounts of genomic data have become available (1, 470). These diseases, a characteristic inoculation eschar at the bite site. How- sequence data have been used to develop specific qPCR primers ever, these signs vary depending on the rickettsial species involved, and probes. In 2012, the WHO Collaborative Center for Rickett- and typical signs may be absent or unnoticed by an undirected sioses and Other Arthropod-Borne Bacterial Diseases reported 2 clinical examination. Therefore, the diagnosis of rickettsioses has years of experience with rickettsial molecular detection using been characterized as a challenge because many physicians are qPCR. All Rickettsia genomes available were compared to discover unfamiliar with the nonspecific symptoms found during the early specific sequences to design new sets of primers and probes. The stages of the illness. Common nonspecific laboratory methods specificity was verified in silico and against a panel of 30 rickettsial and specific methods for the diagnosis of rickettsioses were re- species. Sensitivity was determined by using 10-fold serial dilu- viewed in 2005, including serology, culture, histochemical, and tions. Primers and probes that were both specific and sensitive immunohistochemical methods and molecular tools available at were routinely used for the diagnosis of rickettsial infections from that time (2). New approaches have emerged in recent years. clinical specimens. Sets of primers and probes that could detect R.

686 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

ified with sterile water and placed onto the inoculation eschar for 1 min before swabbing, will increase the quantity of material swabbed. Also, the crust eschar can also be used for rickettsial diagnosis. In 2012, the usefulness of eschar swabs and/or eschar crust samples was reported for the diagnosis of R. africae infection in returning travelers (472). Finally, in 2013, the use of a swab technique to diagnose R. parkeri infection was reported (473).

NEW TOOLS TO IDENTIFY TICKS The removal of a tick from the human body is commonplace. Certain tick species are well-known vectors of human diseases, particularly rickettsioses (Fig. 2). Therefore, identifying the tick species is clinically helpful, as it will alert the physician to the diseases that may have been transmitted. Such information must be obtained quickly. Tick species can be morphologically identi- fied by using taxonomic keys for local species in several geographic regions (474). However, morphological identification can be dif- FIG 16 Use of swabs of skin eschar in the diagnosis of a case of Rickettsia ficult because it requires some entomological expertise. Addition- sibirica mongolitimonae by qPCR. ally, a specimen that is damaged or immature is difficult to iden- tify. Molecular methods, such as the sequencing of mitochondrial DNA, could be used to improve identification; however, there is conorii, R. slovaca, R. africae, and R. australis were retained; 643 currently no PCR assay that can distinguish tick species, and ideal clinical samples were screened for the presence of Rickettsia DNA. PCR primer pairs that can amplify the relevant gene fragments are Compared to traditional detection methods, qPCR assays im- not available. Protein profiling by matrix-assisted laser desorption proved the management of patients with suspected cases of rick- ionization–time of flight mass spectrometry (MALDI-TOF MS) is ettsiosis, with 45 positive samples being detected mainly from cu- now increasingly common for the routine identification of micro- taneous biopsy specimens and swabs (31/45) (469). organisms in clinical microbiology (475). The MALDI-TOF MS In fact, the use of cutaneous swabs from patients rather than approach was recently applied for the differentiation of arthro- cutaneous biopsy specimens for qPCR testing is most likely the pods. Recently, a MALDI-TOF MS study of 7 ticks reported that second major innovation in the diagnosis of tick-borne rickettsi- whole ticks or body parts can generate spectra that are sufficient oses (Fig. 16). Skin biopsy specimens, particularly eschar biopsy for species identification (476). More recently, we found that the specimens, are used for detection of Rickettsia spp. by molecular use of tick legs appears to be an effective means to rapidly identify tools, but this technique is invasive and painful for patients and is tick vectors by MALDI-TOF MS if a reference database is avail- difficult to perform on certain areas of the body. The sample can- able. The remainder of the body can be reserved for other pur- not be obtained by a general practitioner or a family doctor in a poses, such as the detection of pathogens (477). The benefits for consulting room or in a patient’s home. In addition, the sample clinicians include more targeted surveillance of patients for symp- cannot be obtained for epidemiological and clinical research in toms of potentially transmitted diseases and the ability to make developing countries. In 2009, one study reported the usefulness decisions that are more informed as to whether postexposure pro- of swabs of skin lesions in the diagnosis of 3 cases of Queensland phylactic treatment should be administered. tick typhus and 1 case of ATBF (359). To determine the usefulness of the noninvasive cutaneous swab specimens for detecting rick- TREATMENT PERSPECTIVE ettsiae, skin eschars of 6 guinea pigs and 9 humans were tested in Little new data describing antimicrobial therapy of tick-borne 2011. Specimens from eschars in guinea pigs were positive for SFG rickettsioses have been published since 2005, and doxycycline rickettsiae as long as lesions were present, and the efficacy and remains the standard treatment for these infections. This regimen reliability of the skin lesion swabs were shown for the molecular is associated with better outcomes than other regimens (478). It is detection of 6 Rickettsia species. The optimal storage temperature also evident that doxycycline should be used in children present- for specimens was 4°C for 3 days (248). ing with severe rickettsial disease and should be considered by all Eschar swabbing has also been successfully used when a total of physicians in light of its good tolerance. Fluoroquinolones have 39 patients were sampled in Oran, Algeria (471). Swabs were then been presented as an alternative to doxycycline; however, recent sent to and tested in Marseille, France. In this prospective study, R. studies have shown that fluoroquinolones are associated with a conorii was identified in 64% of patients with eschars and rash by deleterious outcome during R. conorii infection in humans and in using this procedure. The opinions of health care providers and a cell culture model, potentially due to the upregulation of a toxin- patients were evaluated. As expected, most health professionals antitoxin module (479, 480). In the future, the impact of fluoro- preferred collecting swab samples over biopsy samples for patients quinolones in retrospective studies of other rickettsioses should be and for themselves. Patients also preferred having a swab sample assessed. However, because we do not recommend the use of fluo- taken over a skin biopsy sample (471). Swabbing of an eschar is roquinolones for the treatment of MSF, prospective studies of easy and painless. Any practitioner at the bedside needs only a other rickettsial diseases seem imprudent. Josamycin and new classic dry sterile swab. It needs to be directed, while rotating vig- macrolide compounds, such as clarithromycin and azithromycin, orously, to the base of the eschar, after removing the crust. If the may represent alternatives for the treatment of some rickettsioses, eschar lesion appears very dry, a wet compress, previously humid- particularly in pregnant women, under strict follow-up and in the

October 2013 Volume 26 Number 4 cmr.asm.org 687 Parola et al. absence of severe disease (478). Telithromycin also seems to be have generated new questions regarding tick-rickettsia associa- highly active in vitro, but in vivo data are lacking; therefore, these tions and interactions and have led to a growing realization that drugs should be evaluated further (478). In any case, early empir- classical tools, particularly microbiological isolation and animal ical antibiotic therapy should be prescribed for any suspected tick- transmission studies, will be needed to better define the roles of transmitted rickettsiosis before confirmation of the diagnosis. ticks as potential reservoirs and vectors. The role as reservoirs would imply that maintenance of rickettsiae relies on both effi- CONCLUSION cient transstadial and transovarial transmission and that rickett- Tick-borne rickettsioses are truly a paradigm for emerging infec- siae have no effect on the reproductive fitness or viability of the tious diseases. Efforts to characterize distinct tick-borne rickettsi- tick host. oses are occurring in regions for which a single pathogenic rick- It is difficult to speculate on if there are still many species and ettsial species has been previously described. Collaborations with subspecies of rickettsiae to discover, including human pathogens, investigators in the tropics and the curiosity of clinicians, com- or if the field is approaching the upper limit of that list. There are bined with powerful diagnostic methods, have continued to in- probably as many as the arthropods in which they reside. crease the recognition of rickettsial organisms, including patho- In the past, it was clear that many rickettsiae were identified in genic organisms. Because ecotourism and adventure travel are ticks long before they were found in humans because the number increasingly popular worldwide, the incidence of travel-associated of DNA copies and the bacterial loads are higher in arthropods tick-borne emerging rickettsioses is likely to increase in the future than in human blood. This search for additional pathogens in (385, 387, 481). arthropods remains an essential element of the discovery of the Rickettsiae are difficult to grow, and serological techniques next pathogenic rickettsioses in humans. lead to cross-reactions that often cannot differentiate Rickettsia species. Only the serological technique of Western blotting with ACKNOWLEDGMENTS cross-absorption can help in this situation, and this technique is We are grateful to Roshan Padmanabhan for his help in making Fig. 1. limited in routine practice to the laboratory of the WHO Collab- The findings and conclusions are those of the authors and do not orative Center for Rickettsioses and Other Arthropod-Borne Bac- necessarily represent the official position of the Centers for Disease Con- terial Diseases in Marseille, France. trol and Prevention. A diagnostic revolution has resulted from the introduction of molecular methods. The use of qPCR is widespread and inexpen- REFERENCES sive and reduces the delay in the diagnosis of rickettsial infections. 1. Merhej V, Raoult D. 2011. Rickettsial evolution in the light of compar- These real-time PCR assays could be implemented easily in labo- ative genomics. Biol. Rev. Camb. Philos. Soc. 86:379–405. ratories that have molecular biology facilities and may be added to 2. Parola P, Paddock CD, Raoult D. 2005. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin. Mi- existing molecular tools as a point-of-care strategy (482). crobiol. Rev. 18:719–756. Another major step forward in recent years has been the prac- 3. Fujita H, Fournier PE, Takada N, Saito T, Raoult D. 2006. Rickettsia tice of swabbing eschars rather than excisional biopsy techniques. asiatica sp. nov., isolated in Japan. Int. J. Syst. Evol. Microbiol. 56:2365– This method has proved effective in the diagnosis of infections by 2368. R. australis, R. parkeri, R. africae, R. conorii, and R. sibirica subsp. 4. Euzéby J. 2006. Validation list no. 108. Int. J. Syst. Evol. Microbiol. 56:499–500. mongolitimonae. This nontraumatic approach can be used to sam- 5. Duh D, Punda-Polic V, Avsic-Zupanc T, Bouyer D, Walker DH, ple lesional material even in sensitive sites such as eyes or genitalia Popov VL, Jelovsek M, Gracner M, Trilar T, Bradaric N, Kurtti TJ, and ultimately may contribute to an increase in the recognized Strus J. 2010. Rickettsia hoogstraalii sp. nov., isolated from hard- and spectrum of infections associated with Rickettsia species. This soft-bodied ticks. Int. J. Syst. Evol. Microbiol. 60:977–984. 6. Mediannikov O, Matsumoto K, Samoylenko I, Drancourt M, Roux V, technique has a high acceptance rate for clinicians and patients Rydkina E, Davoust B, Tarasevich I, Brouqui P, Fournier PE. 2008. because the test is easily performed and is considerably less inva- Rickettsia raoultii sp. nov., a spotted fever group rickettsia associated with sive than a conventional skin biopsy. Moreover, this test can be Dermacentor ticks in Europe and Russia. Int. J. Syst. Evol. Microbiol. applied in large epidemiological and clinical studies in developing 58:1635–1639. countries. 7. Fournier PE, Takada N, Fujita H, Raoult D. 2006. Rickettsia tamurae sp. nov., isolated from Amblyomma testudinarium ticks. Int. J. Syst. Evol. Regarding ticks and rickettsioses, many points remain to be Microbiol. 56:1673–1675. clarified. It appears that in humans, most rickettsioses are associ- 8. Zhu Y, Fournier PE, Eremeeva M, Raoult D. 2005. Proposal to create ated with clinical and epidemiological features that skillful clini- subspecies of Rickettsia conorii based on multi-locus sequence typing and cians should be able to identify. Among these features are skin an emended description of Rickettsia conorii. BMC Microbiol. 5:11. doi: 10.1186/1471-2180-5-11. manifestations that include the type and location of the rash, in- 9. Fournier PE, Zhu Y, Yu X, Raoult D. 2006. Proposal to create subspe- oculation eschars, and lymphangitis. The seasonality of infection cies of Rickettsia sibirica and an emended description of Rickettsia si- and the number of tick bites change depending on the geographic birica. Ann. N. Y. Acad. Sci. 1078:597–606. location and the degree of aggression exhibited by the ticks, the 10. Fournier PE, Dumler JS, Greub G, Zhang J, Wu Y, Raoult D. 2003. degree of host specificity, and environmental factors such as tem- Gene sequence-based criteria for identification of new rickettsia isolates and description of Rickettsia heilongjiangensis sp. nov. J. Clin. Microbiol. perature and humidity. Rhipicephalus sanguineus ticks appear to 41:5456–5465. be more prone to biting humans when ambient temperatures are 11. Klenk HP, Goker M. 2010. En route to a genome-based classification of relatively warm and rarely bite humans when temperatures are Archaea and Bacteria? Syst. Appl. Microbiol. 33:175–182. cooler. The reason why certain ticks, such as Dermacentor species, 12. Merhej V, Royer-Carenzi M, Pontarotti P, Raoult D. 2009. Massive comparative genomic analysis reveals convergent evolution of special- bite more readily during the cool season in Europe remains un- ized bacteria. Biol. Direct 4:13. doi:10.1186/1745-6150-4-13. known. 13. Fournier PE, El Karkouri K, Leroy Q, Robert C, Giumelli B, Renesto Recent articles describing the detection of rickettsiae in ticks P, Socolovschi C, Parola P, Audic S, Raoult D. 2009. Analysis of the

688 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

Rickettsia africae genome reveals that virulence acquisition in Rickettsia ing Amblyomma auricularium ticks in Pernambuco, northeastern Brazil: species may be explained by genome reduction. BMC Genomics 10:166. isolation, transovarial transmission, and transstadial perpetuation. Vec- doi:10.1186/1471-2164-10-166. tor Borne Zoonotic Dis. [Epub ahead of print.] doi:10.1089/vbz.2012 14. Baldridge GD, Burkhardt NY, Felsheim RF, Kurtti TJ, Munderloh UG. .1223. 2008. Plasmids of the pRM/pRF family occur in diverse Rickettsia species. 33. Medina-Sanchez A, Bouyer DH, Alcantara-Rodriguez V, Mafra C, Appl. Environ. Microbiol. 74:645–652. Zavala-Castro J, Whitworth T, Popov VL, Fernandez-Salas I, Walker 15. Fournier PE, Belghazi L, Robert C, Elkarkouri K, Richards AL, Greub DH. 2005. Detection of a typhus group Rickettsia in Amblyomma ticks in G, Collyn F, Ogawa M, Portillo A, Oteo JA, Psaroulaki A, Bitam I, the state of Nuevo Leon, Mexico. Ann. N. Y. Acad. Sci. 1063:327–332. Raoult D. 2008. Variations of plasmid content in Rickettsia felis. PLoS 34. Parola P. 2011. Rickettsia felis: from a rare disease in the USA to a com- One 3:e2289. doi:10.1371/journal.pone.0002289. mon cause of fever in sub-Saharan Africa. Clin. Microbiol. Infect. 17: 16. Ogata H, La Scola B, Audic S, Renesto P, Blanc G, Robert C, Fournier 996–1000. PE, Claverie JM, Raoult D. 2006. Genome sequence of Rickettsia bellii 35. Socolovschi C, Audoly G, Raoult D. 2013. Connection of toxin- illuminates the role of amoebae in gene exchanges between intracellular antitoxin modules to inoculation eschar and arthropod vertical trans- pathogens. PLoS Genet. 2:e76. doi:10.1371/journal.pgen.0020076. mission in Rickettsiales. Comp. Immunol. Microbiol. Infect. Dis. 36: 17. Ogata H, Renesto P, Audic S, Robert C, Blanc G, Fournier PE, 199–209. Parinello H, Claverie JM, Raoult D. 2005. The genome sequence of 36. Davoust B, Mediannikov O, Marie JL, Socolovschi C, Parola P, Raoult Rickettsia felis identifies the first putative conjugative plasmid in an obli- D. 2010. Are vertebrates reservoir hosts for Rickettsia? Bull. Acad. Vet. gate intracellular parasite. PLoS Biol. 3:e248. doi:10.1371/journal.pbio France 163:291–302. .0030248. 37. Levin ML, Killmaster LF, Zemtsova GE. 2012. Domestic dogs (Canis 18. Merhej V, Notredame C, Royer-Carenzi M, Pontarotti P, Raoult D. familiaris) as reservoir hosts for Rickettsia conorii. Vector Borne Zoonotic 2011. The rhizome of life: the sympatric Rickettsia felis paradigm dem- Dis. 12:28–33. onstrates the random transfer of DNA sequences. Mol. Biol. Evol. 28: 38. Zemtsova G, Killmaster LF, Mumcuoglu KY, Levin ML. 2010. Co- 3213–3223. feeding as a route for transmission of Rickettsia conorii israelensis between 19. Socolovschi C, Mediannikov O, Raoult D, Parola P. 2009. The rela- Rhipicephalus sanguineus ticks. Exp. Appl. Acarol. 52:383–392. tionship between spotted fever group Rickettsiae and ixodid ticks. Vet. 39. Horta MC, Moraes-Filho J, Casagrande RA, Saito TB, Rosa SC, Ogrze- Res. 40:34. doi:10.1051/vetres/2009017. walska M, Matushima ER, Labruna MB. 2009. Experimental infection 20. Socolovschi C, Matsumoto K, Brouqui P, Raoult D, Parola P. 2009. of opossums Didelphis aurita by Rickettsia rickettsii and evaluation of the Experimental infection of Rhipicephalus sanguineus with Rickettsia cono- transmission of the infection to ticks Amblyomma cajennense. Vector rii conorii. Clin. Microbiol. Infect. 15(Suppl 2):324–325. Borne Zoonotic Dis. 9:109–118. 21. Levin ML, Killmaster L, Eremeeva ME, Dasch GA. 2009. Effects of 40. Souza CE, Moraes-Filho J, Ogrzewalska M, Uchoa FC, Horta MC, Rickettsia conorii infection on the survival of Rhipicephalus sanguineus Souza SS, Borba RC, Labruna MB. 2009. Experimental infection of ticks. Clin. Microbiol. Infect. 15(Suppl 2):277–278. capybaras Hydrochoerus hydrochaeris by Rickettsia rickettsii and evalua- 22. Matsumoto K, Brouqui P, Raoult D, Parola P. 2005. Experimental tion of the transmission of the infection to ticks Amblyomma cajennense. infection models of ticks of the Rhipicephalus sanguineus group with Vet. Parasitol. 161:116–121. Rickettsia conorii. Vector Borne Zoonotic Dis. 5:363–372. 41. Reye AL, Arinola OG, Hubschen JM, Muller CP. 2012. Pathogen 23. Levin ML, Killmaster L, Zemtsova G, Grant D, Mumcuoglu KY, prevalence in ticks collected from the vegetation and livestock in Nigeria. Eremeeva ME, Dasch GA. 2009. Incongruent effects of two isolates of Appl. Environ. Microbiol. 78:2562–2568. Rickettsia conorii on the survival of Rhipicephalus sanguineus ticks. Exp. 42. Ortuno A, Pons I, Quesada M, Lario S, Anton E, Gil A, Castella J, Appl. Acarol. 49:347–359. Segura F. 2012. Evaluation of the presence of Rickettsia slovaca infection 24. Socolovschi C, Bitam I, Raoult D, Parola P. 2009. Transmission of in domestic ruminants in Catalonia, Northeastern Spain. Vector Borne Rickettsia conorii conorii in naturally infected Rhipicephalus sanguineus. Zoonotic Dis. 12:1019–1022. Clin. Microbiol. Infect. 15(Suppl 2):319–321. 25. Socolovschi C, Gaudart J, Bitam I, Huynh TP, Raoult D, Parola P. 43. Ortuno A, Quesada M, Lopez-Claessens S, Castella J, Sanfeliu I, Anton 2012. Why are there so few Rickettsia conorii conorii-infected Rhipiceph- E, Segura-Porta F. 2007. The role of wild boar (Sus scrofa) in the eco- alus sanguineus ticks in the wild? PLoS Negl. Trop. Dis. 6:e1697. doi:10 epidemiology of R. slovaca in Northeastern Spain. Vector Borne Zoo- .1371/journal.pntd.0001697. notic Dis. 7:59–64. 26. Piranda EM, Faccini JL, Pinter A, Pacheco RC, Cancado PH, Labruna 44. Inokuma H, Seino N, Suzuki M, Kaji K, Takahashi H, Igota H, Inoue MB. 2011. Experimental infection of Rhipicephalus sanguineus ticks with S. 2008. Detection of Rickettsia helvetica DNA from peripheral blood of the bacterium Rickettsia rickettsii, using experimentally infected dogs. sika deer (Cervus nippon yesoensis) in Japan. J. Wildl. Dis. 44:164–167. Vector Borne Zoonotic Dis. 11:29–36. 45. La Scola B, Bechah Y, Lepidi H, Raoult D. 2009. Prediction of rickett- 27. Soares JF, Soares HS, Barbieri AM, Labruna MB. 2012. Experimental sial skin eschars in humans using an experimental guinea pig model. infection of the tick Amblyomma cajennense, Cayenne tick, with Rickett- Microb. Pathog. 47:128–133. sia rickettsii, the agent of Rocky Mountain spotted fever. Med. Vet. En- 46. Chapman AS, Murphy SM, Demma LJ, Holman RC, Curns AT, tomol. 26:139–151. McQuiston JH, Krebs JW, Swerdlow DL. 2006. Rocky Mountain spot- 28. Pacheco RC, Moraes-Filho J, Guedes E, Silveira I, Richtzenhain LJ, ted fever in the United States, 1997-2002. Vector Borne Zoonotic Dis. Leite RC, Labruna MB. 2011. Rickettsial infections of dogs, horses and 6:170–178. ticks in Juiz de Fora, southeastern Brazil, and isolation of Rickettsia rick- 47. Chen LF, Sexton DJ. 2008. What’s new in Rocky Mountain spotted ettsii from Rhipicephalus sanguineus ticks. Med. Vet. Entomol. 25:148– fever? Infect. Dis. Clin. North Am. 22:415–432. 155. 48. Childs JE, Paddock CD. 2007. Rocky Mountain spotted fever, p 97–116. 29. Labruna MB, Ogrzewalska M, Soares JF, Martins TF, Soares HS, In Raoult D, Parola P (ed), Rickettsial diseases. Informa Healthcare, New Moraes-Filho J, Nieri-Bastos FA, Almeida AP, Pinter A. 2011. Exper- York, NY. imental infection of Amblyomma aureolatum ticks with Rickettsia rickett- 49. Dantas-Torres F. 2007. Rocky Mountain spotted fever. Lancet Infect. sii. Emerg. Infect. Dis. 17:829–834. Dis. 7:724–732. 30. Socolovschi C, Huynh TP, Davoust B, Gomez J, Raoult D, Parola P. 50. Estripeaut D, Aramburu MG, Saez-Llorens X, Thompson HA, Dasch 2009. Transovarial and trans-stadial transmission of Rickettsiae africae in GA, Paddock CD, Zaki S, Eremeeva ME. 2007. Rocky Mountain spot- Amblyomma variegatum ticks. Clin. Microbiol. Infect. 15(Suppl 2):317– ted fever, Panama. Emerg. Infect. Dis. 13:1763–1765. 318. 51. Hun L, Cortes X, Taylor L. 2008. Molecular characterization of Rick- 31. Horta MC, Pinter A, Schumaker TT, Labruna MB. 2006. Natural ettsia rickettsii isolated from human clinical samples and from the rabbit infection, transovarial transmission, and transstadial survival of Rickett- tick Haemaphysalis leporispalustris collected at different geographic sia bellii in the tick Ixodes loricatus (: ) from Brazil. Ann. zones in Costa Rica. Am. J. Trop. Med. Hyg. 79:899–902. N. Y. Acad. Sci. 1078:285–290. 52. Eremeeva ME, Berganza E, Suarez G, Gobern L, Dueger E, Castillo L, 32. Saraiva DG, Nieri-Bastos FA, Horta MC, Soares HS, Nicola PA, Reyes L, Wikswo ME, Abramowicz KF, Dasch GA, Lindblade KA. Pereira LCM, Labruna MB. 24 May 2013. Rickettsia amblyommii infect- 2013. Investigation of an outbreak of rickettsial febrile illness in Guate-

October 2013 Volume 26 Number 4 cmr.asm.org 689 Parola et al.

mala, 2007. Int. J. Infect. Dis. 17:e304–e311. doi:10.1016/j.ijid.2012.11 rickettsial agents in ticks from domestic mammals in eastern Panama. J. .011. Med. Entomol. 46:856–861. 53. Openshaw JJ, Swerdlow DL, Krebs JW, Holman RC, Mandel E, Har- 73. Oliveira KA, Pinter A, Medina-Sanchez A, Boppana VD, Wikel SK, vey A, Haberling D, Massung RF, McQuiston JH. 2010. Rocky moun- Saito TB, Shelite T, Blanton L, Popov V, Teel PD, Walker DH, Galvao tain spotted fever in the United States, 2000-2007: interpreting contem- MA, Mafra C, Bouyer DH. 2010. Amblyomma imitator ticks as vectors of porary increases in incidence. Am. J. Trop. Med. Hyg. 83:174–182. Rickettsia rickettsii, Mexico. Emerg. Infect. Dis. 16:1282–1284. 54. Demma LJ, Traeger MS, Nicholson WL, Paddock CD, Blau DM, 74. Berrada ZL, Goethert HK, Cunningham J, Telford SR, III. 2011. Eremeeva ME, Dasch GA, Levin ML, Singleton J, Jr, Zaki SR, Cheek Rickettsia rickettsii (Rickettsiales: Rickettsiaceae) in Amblyomma ameri- JE, Swerdlow DL, McQuiston JH. 2005. Rocky Mountain spotted fever canum (Acari: Ixodidae) from Kansas. J. Med. Entomol. 48:461–467. from an unexpected tick vector in Arizona. N. Engl. J. Med. 353:587–594. 75. Breitschwerdt EB, Hegarty BC, Maggi RG, Lantos PM, Aslett DM, 55. Demma LJ, Holman RC, Mikosz CA, Curns AT, Swerdlow DL, Pai- Bradley JM. 2011. Rickettsia rickettsii transmission by a lone star tick, sano EL, Cheek JE. 2006. Rocky Mountain spotted fever hospitalizations North Carolina. Emerg. Infect. Dis. 17:873–875. among American Indians. Am. J. Trop. Med. Hyg. 75:537–541. 76. Wikswo ME, Hu R, Dasch GA, Krueger L, Arugay A, Jones K, Hess B, 56. Nicholson WL, Paddock CD, Demma L, Traeger M, Johnson B, Bennett S, Kramer V, Eremeeva ME. 2008. Detection and identification Dickson J, McQuiston J, Swerdlow D. 2006. Rocky Mountain spotted of spotted fever group rickettsiae in Dermacentor species from southern fever in Arizona: documentation of heavy environmental infestations of California. J. Med. Entomol. 45:509–516. Rhipicephalus sanguineus at an endemic site. Ann. N. Y. Acad. Sci. 1078: 77. Dergousoff SJ, Gajadhar AJ, Chilton NB. 2009. Prevalence of Rickettsia 338–341. species in Canadian populations of Dermacentor andersoni and D. varia- 57. Nicholson WL, Gordon R, Demma LJ. 2006. Spotted fever group bilis. Appl. Environ. Microbiol. 75:1786–1789. rickettsial infection in dogs from eastern Arizona: how long has it been 78. Moncayo AC, Cohen SB, Fritzen CM, Huang E, Yabsley MJ, Freye JD, there? Ann. N. Y. Acad. Sci. 1078:519–522. Dunlap BG, Huang J, Mead DG, Jones TF, Dunn JR. 2010. Absence of 58. McQuiston JH, Guerra MA, Watts MR, Lawaczeck E, Levy C, Nich- Rickettsia rickettsii and occurrence of other spotted fever group rickett- olson WL, Adjemian J, Swerdlow DL. 2011. Evidence of exposure to siae in ticks from Tennessee. Am. J. Trop. Med. Hyg. 83:653–657. spotted fever group rickettsiae among Arizona dogs outside a previously 79. Fritzen CM, Huang J, Westby K, Freye JD, Dunlap B, Yabsley MJ, documented outbreak area. Zoonoses Public Health 58:85–92. Schardein M, Dunn JR, Jones TF, Moncayo AC. 2011. Infection prev- 59. Bustamente Moreno JG, Pon Méndez A. 2010. Actualización en la alences of common tick-borne pathogens in adult lone star ticks vigilancia epidemiológica de “rickettsiosis.” Part I. Epidemiol. Bol. (Amblyomma americanum) and American dog ticks (Dermacentor varia- 6:1–4. bilis) in Kentucky. Am. J. Trop. Med. Hyg. 85:718–723. 60. Bustamente Moreno JG, Pon Méndez A. 2010. Actualización en la 80. Stromdahl EY, Jiang J, Vince M, Richards AL. 2011. Infrequency of vigilancia epidemiológica de “rickettsiosis.” Part II. Epidemiol. Bol. Rickettsia rickettsii in Dermacentor variabilis removed from humans, with 7:1–3. comments on the role of other human-biting ticks associated with spot- 61. Baty S, McElroy K, Levy C, Nicholson W, McQuiston J. 2011. Emer- ted fever group rickettsiae in the United States. Vector Borne Zoonotic gence of a new focus of Rocky Mountain spotted fever—south central Dis. 11:969–977. Arizona, 2009-2010, p 121. Abstr. 60th Annu. Epidemic Intell. Serv. 81. Eremeeva ME, Bosserman E, Zambrano M, Demma L, Dasch GA. Conf., Atlanta, GA. 2006. Molecular typing of novel Rickettsia rickettsii isolates from Arizona. 62. Holman RC, McQuiston JH, Haberling DL, Cheek JE. 2009. Increasing Ann. N. Y. Acad. Sci. 1078:573–577. incidence of Rocky Mountain spotted fever among the American Indian 82. Garrison LE, Kelly R, Nicholson WL, Eremeeva ME. 2007. Tick sur- population in the United States. Am. J. Trop. Med. Hyg. 80:601–605. veillance notes: Rickettsia rickettsii in Rhipicephalus sanguineus from Gor- 63. Dahlgren FS, Holman RC, Paddock CD, Callinan LS, McQuiston JH. don County. Georgia Epidemiol. Rep. 23:1–2. 2012. Fatal Rocky Mountain spotted fever in the United States, 1999- 83. Eremeeva ME, Zambrano ML, Anaya L, Beati L, Karpathy SE, Santos- 2007. Am. J. Trop. Med. Hyg. 86:713–719. Silva MM, Salceda B, MacBeth D, Olguin H, Dasch GA, Aranda CA. 64. Folkema AM, Holman RC, McQuiston JH, Cheek JE. 2012. Trends in 2011. Rickettsia rickettsii in Rhipicephalus ticks, Mexicali, Mexico. J. Med. clinical diagnoses of Rocky Mountain spotted fever among American Entomol. 48:418–421. Indians, 2001-2008. Am. J. Trop. Med. Hyg. 86:152–158. 84. Carmichael JR, Fuerst PA. 2006. A rickettsial mixed infection in a 65. Paddock CD, Telford SRI. 2011. Through a glass, darkly: the global Dermacentor variabilis tick from Ohio. Ann. N. Y. Acad. Sci. 1078:334– incidence of tick-borne diseases, p 221–266. In Institute of Medicine 337. (ed), Critical needs and gaps in understanding prevention, amelioration, 85. Arguello AP, Hun L, Rivera P, Taylor L. 2012. A fatal urban case of and resolution of Lyme and other tick-borne diseases: the short-term and Rocky Mountain spotted fever presenting an eschar in San Jose, Costa long-term outcomes. National Academies Press, Washington, DC. Rica. Am. J. Trop. Med. Hyg. 87:345–348. 66. Paddock CD. 2005. Rickettsia parkeri as a paradigm for multiple causes 86. Minniear TD, Buckingham SC. 2009. Managing Rocky Mountain spot- of tick-borne spotted fever in the Western Hemisphere. Ann. N. Y. Acad. ted fever. Expert Rev. Anti Infect. Ther. 7:1131–1137. Sci. 1063:315–326. 87. Buckingham SC, Marshall GS, Schutze GE, Woods CR, Jackson MA, 67. Whitman TJ, Richards AL, Paddock CD, Tamminga CL, Sniezek PJ, Patterson LE, Jacobs RF. 2007. Clinical and laboratory features, hospital Jiang J, Byers DK, Sanders JW. 2007. Rickettsia parkeri infection after course, and outcome of Rocky Mountain spotted fever in children. J. tick bite, Virginia. Emerg. Infect. Dis. 13:334–336. Pediatr. 150:180–184. 68. Paddock CD, Finley RW, Wright CS, Robinson HN, Schrodt BJ, Lane 88. Martinez-Medina MA, Alvarez-Hernandez G, Padilla-Zamudioa JG, CC, Ekenna O, Blass MA, Tamminga CL, Ohl CA, McLellan SL, Rojas-Guerra MG. 2007. Rocky Mountain spotted fever in children: Goddard J, Holman RC, Openshaw JJ, Sumner JW, Zaki SR, Eremeeva clinical and epidemiological features. Gac. Med. Mex. 143:137–140. (In ME. 2008. Rickettsia parkeri rickettsiosis and its clinical distinction from Spanish.) Rocky Mountain spotted fever. Clin. Infect. Dis. 47:1188–1196. 89. Zavala-Castro JE, Dzul-Rosado KR, Leon JJ, Walker DH, Zavala- 69. Cragun WC, Bartlett BL, Ellis MW, Hoover AZ, Tyring SK, Mendoza Velazquez JE. 2008. An increase in human cases of spotted fever rickett- N, Vento TJ, Nicholson WL, Eremeeva ME, Olano JP, Rapini RP, siosis in Yucatan, Mexico, involving children. Am. J. Trop. Med. Hyg. Paddock CD. 2010. The expanding spectrum of eschar-associated rick- 79:907–910. ettsioses in the United States. Arch. Dermatol. 146:641–648. 90. Sanchez R, Alpuche C, Lopez-Gatell H, Soria C, Estrada J, Olguin H, 70. Centers for Disease Control and Prevention. 2010. Spotted fever rick- Lezana MA, Nicholson W, Eremeeva M, CDC Infectious Disease ettsioses 2010 case definition. Centers for Disease Control and Preven- Pathology Branch, Dasch G, Fonseca M, Montiel S, Waterman S, tion, Atlanta, GA. http://www.cdc.gov/osels/ph_surveillance/nndss McQuiston J. 2009. Rhipicephalus sanguineus-associated Rocky Moun- /casedef/spottedfever_current.htm. Accessed 5 October 2012. tain spotted fever in Mexicali, Mexico: observations from an outbreak in 71. Parola P, Labruna MB, Raoult D. 2009. Tick-borne rickettsioses in 2008-2009, abstr 75. Abstr. 23rd Meet. Am. Soc. Rickettsiol., Hilton America: unanswered questions and emerging diseases. Curr. Infect. Dis. Head, SC, 15 to 18 August 2009. Rep. 11:40–50. 91. Alvarez-Hernandez G. 2010. Rocky Mountain spotted fever, a forgotten 72. Bermudez SE, Eremeeva ME, Karpathy SE, Samudio F, Zambrano ML, epidemic. Salud Publica Mex. 52(1):1–3. (In Spanish.) Zaldivar Y, Motta JA, Dasch GA. 2009. Detection and identification of 92. Tribaldos M, Zaldivar Y, Bermudez S, Samudio F, Mendoza Y, Mar-

690 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

tinez AA, Villalobos R, Eremeeva ME, Paddock CD, Page K, Smith RE, africae in Amblyomma variegatum and domestic ruminants on eight Ca- Pascale JM. 2011. Rocky Mountain spotted fever in Panama: a cluster ribbean islands. J. Parasitol. 96:1086–1088. description. J. Infect. Dev. Ctries. 5:737–741. 116. Owen CE, Bahrami S, Malone JC, Callen JP, Kulp-Shorten CL. 2006. 93. Karpathy SE, Dasch GA, Eremeeva ME. 2007. Molecular typing of African tick bite fever: a not-so-uncommon illness in international trav- isolates of Rickettsia rickettsii by use of DNA sequencing of variable in- elers. Arch. Dermatol. 142:1312–1314. tergenic regions. J. Clin. Microbiol. 45:2545–2553. 117. McQuade J, Cather JC. 2006. Fever and malaise associated with a painful 94. Eremeeva ME, Dasch GA. 2009. Closing the gaps between genotype and papule on the ankle. Proc. Bayl. Univ. Med. Cent. 19:49–51. phenotype in Rickettsia rickettsii. Ann. N. Y. Acad. Sci. 1166:12–26. 118. Freedman DO, Weld LH, Kozarsky PE, Fisk T, Robins R, von Son- 95. Sumner JW, Durden LA, Goddard J, Stromdahl EY, Clark KL, Reeves nenburg F, Keystone JS, Pandey P, Cetron MS. 2006. Spectrum of WK, Paddock CD. 2007. Gulf Coast ticks (Amblyomma maculatum) and disease and relation to place of exposure among ill returned travelers. N. Rickettsia parkeri, United States. Emerg. Infect. Dis. 13:751–753. Engl. J. Med. 354:119–130. 96. Paddock CD, Fournier PE, Sumner JW, Goddard J, Elshenawy Y, 119. Shapiro MR, Fritz CL, Tait K, Paddock CD, Nicholson WL, Abramo- Metcalfe MG, Loftis AD, Varela-Stokes A. 2010. Isolation of Rickettsia wicz KF, Karpathy SE, Dasch GA, Sumner JW, Adem PV, Scott JJ, parkeri and identification of a novel spotted fever group Rickettsia sp. Padgett KA, Zaki SR, Eremeeva ME. 2010. Rickettsia 364D: a newly from Gulf Coast ticks (Amblyomma maculatum) in the United States. recognized cause of eschar-associated illness in California. Clin. Infect. Appl. Environ. Microbiol. 76:2689–2696. Dis. 50:541–548. 97. Trout R, Steelman CD, Szalanski AL, Williamson PC. 2010. Rickettsiae 120. Mediannikov O, Parola P, Raoult D. 2007. Other tick-borne rickettsi- in Gulf Coast ticks, Arkansas, USA. Emerg. Infect. Dis. 16:830–832. oses, p 139–163. In Raoult D, Parola P (ed), Rickettsial diseases. Informa 98. Wright CL, Nadolny RM, Jiang J, Richards AL, Sonenshine DE, Gaff Healthcare, New York, NY. HD, Hynes WL. 2011. Rickettsia parkeri in Gulf Coast ticks, southeastern 121. Eremeeva ME, Madan A, Shaw CD, Tang K, Dasch GA. 2005. New Virginia, USA. Emerg. Infect. Dis. 17:896–898. perspectives on rickettsial evolution from new genome sequences of rick- 99. Fornadel CM, Zhang X, Smith JD, Paddock CD, Arias JR, Norris DE. ettsia, particularly R. canadensis, and . Ann. N. Y. 2011. High rates of Rickettsia parkeri infection in Gulf Coast ticks Acad. Sci. 1063:47–63. (Amblyomma maculatum) and identification of “Candidatus Rickettsia 122. Yabsley MJ, Nims TN, Savage MY, Durden LA. 2009. Ticks and andeanae” from Fairfax County, Virginia. Vector Borne Zoonotic Dis. tick-borne pathogens and putative symbionts of black bears (Ursus 11:1535–1539. americanus floridanus) from Georgia and Florida. J. Parasitol. 95:1125– 100. Varela-Stokes AS, Paddock CD, Engber B, Toliver M. 2011. Rickettsia 1128. parkeri in Amblyomma maculatum ticks, North Carolina, USA, 2009- 123. McQuiston JH, Zemtsova G, Perniciaro J, Hutson M, Singleton J, 2010. Emerg. Infect. Dis. 17:2350–2353. Nicholson WL, Levin ML. 2012. Afebrile spotted fever group Rickettsia 101. Ferrari FA, Goddard J, Paddock CD, Varela-Stokes AS. 2012. Rickettsia infection after a bite from a Dermacentor variabilis tick infected with parkeri and Candidatus Rickettsia andeanae in Gulf Coast ticks, Missis- Rickettsia montanensis. Vector Borne Zoonotic. Dis. 12:1059–1061. sippi, USA. Emerg. Infect. Dis. 18:1705–1707. 124. Kurtti TJ, Simser JA, Baldridge GD, Palmer AT, Munderloh UG. 2005. 102. Edwards KT, Goddard J, Varela-Stokes A. 2011. Distribution of spotted Factors influencing in vitro infectivity and growth of Rickettsia peacockii fever group rickettsiae in select tissues of experimentally infected and (Rickettsiales: Rickettsiaceae), an endosymbiont of the Rocky Mountain field-collected Gulf Coast ticks. J. Med. Entomol. 48:687–690. wood tick, Dermacentor andersoni (Acari, Ixodidae). J. Invertebr. Pathol. 103. Cohen SB, Yabsley MJ, Garrison LE, Freye JD, Dunlap BG, Dunn JR, 90:177–186. Mead DG, Jones TF, Moncayo AC. 2009. Rickettsia parkeri in Ambly- 125. Simser JA, Rahman MS, Dreher-Lesnick SM, Azad AF. 2005. A novel omma americanum ticks, Tennessee and Georgia, USA. Emerg. Infect. and naturally occurring transposon, ISRpe1 in the Rickettsia peacockii Dis. 15:1471–1473. genome disrupting the rickA gene involved in actin-based motility. Mol. 104. Williamson PC, Billingsley PM, Teltow GJ, Seals JP, Turnbough MA, Microbiol. 58:71–79. Atkinson SF. 2010. Borrelia, Ehrlichia, and Rickettsia spp. in ticks re- 126. Felsheim RF, Kurtti TJ, Munderloh UG. 2009. Genome sequence of the moved from persons, Texas, USA. Emerg. Infect. Dis. 16:441–446. endosymbiont Rickettsia peacockii and comparison with virulent Rickett- 105. Edwards KT, Goddard J, Jones TL, Paddock CD, Varela-Stokes AS. sia rickettsii: identification of virulence factors. PLoS One 4:e8361. doi: 2011. Cattle and the natural history of Rickettsia parkeri in Mississippi. 10.1371/journal.pone.0008361. Vector Borne Zoonotic Dis. 11:485–491. 127. Clay K, Klyachko O, Grindle N, Civitello D, Oleske D, Fuqua C. 2008. 106. Grasperge BJ, Wolfson W, Macaluso KR. 2012. Rickettsia parkeri infec- Microbial communities and interactions in the lone star tick, Ambly- tion in domestic dogs, Southern Louisiana, USA, 2011. Emerg. Infect. omma americanum. Mol. Ecol. 17:4371–4381. Dis. 18:995–997. 128. Heise SR, Elshahed MS, Little SE. 2010. Bacterial diversity in Ambly- 107. Raoult D, Paddock CD. 2005. Rickettsia parkeri infection and other omma americanum (Acari: Ixodidae) with a focus on members of the spotted fevers in the United States. N. Engl. J. Med. 353:626–627. genus Rickettsia. J. Med. Entomol. 47:258–268. 108. Paddock CD. 2009. The science and fiction of emerging rickettsioses. 129. Jiang J, Yarina T, Miller MK, Stromdahl EY, Richards AL. 2010. Ann. N. Y. Acad. Sci. 1166:133–143. Molecular detection of Rickettsia amblyommii in Amblyomma america- 109. Chen LH, Wilson ME. 2009. Tick-borne rickettsiosis in traveler return- num parasitizing humans. Vector Borne Zoonotic Dis. 10:329–340. ing from Honduras. Emerg. Infect. Dis. 15:1321–1323. 130. Zanettii AS, Pornwiroon W, Kearney MT, Macaluso KR. 2008. Char- 110. Eremeeva ME, Bosserman EA, Demma LJ, Zambrano ML, Blau DM, acterization of rickettsial infection in Amblyomma americanum (Acari: Dasch GA. 2006. Isolation and identification of Rickettsia massiliae from Ixodidae) by quantitative real-time polymerase chain reaction. J. Med. Rhipicephalus sanguineus ticks collected in Arizona. Appl. Environ. Mi- Entomol. 45:267–275. crobiol. 72:5569–5577. 131. Mixson TR, Campbell SR, Gill JS, Ginsberg HS, Reichard MV, Schulze 111. Beeler E, Abramowicz KF, Zambrano ML, Sturgeon MM, Khalaf N, TL, Dasch GA. 2006. Prevalence of Ehrlichia, Borrelia, and rickettsial Hu R, Dasch GA, Eremeeva ME. 2011. A focus of dogs and Rickettsia agents in Amblyomma americanum (Acari: Ixodidae) collected from nine massiliae-infected Rhipicephalus sanguineus in California. Am. J. Trop. states. J. Med. Entomol. 43:1261–1268. Med. Hyg. 84:244–249. 132. Smith MP, Ponnusamy L, Jiang J, Ayyash LA, Richards AL, Apperson 112. Wikswo ME, Hu R, Metzger ME, Eremeeva ME. 2007. Detection of CS. 2010. Bacterial pathogens in Ixodid ticks from a Piedmont County in Rickettsia rickettsii and henselae in Rhipicephalus sanguineus North Carolina: prevalence of rickettsial organisms. Vector Borne Zoo- ticks from California. J. Med. Entomol. 44:158–162. notic Dis. 10:939–952. 113. Kelly PJ. 2006. Rickettsia africae in the West Indies. Emerg. Infect. Dis. 133. Schulze TL, Jordan RA, White JC, Roegner VE, Healy SP. 2011. 12:224–226. Geographical distribution and prevalence of selected Borrelia, Ehrlichia, 114. Robinson JB, Eremeeva ME, Olson PE, Thornton SA, Medina MJ, and Rickettsia infections in Amblyomma americanum (Acari: Ixodidae) Sumner JW, Daschi GA. 2009. New approaches to detection and iden- in New Jersey. J. Am. Mosq. Control Assoc. 27:236–244. tification of Rickettsia africae and Ehrlichia ruminantium in Amblyomma 134. Zhang X, Ren X, Norris DE, Rasgon JL. 2012. Distribution and infec- variegatum (Acari: Ixodidae) ticks from the Caribbean. J. Med. Entomol. tion frequency of ‘Candidatus Rickettsia amblyommii’ in Maryland pop- 46:942–951. ulations of the lone star tick (Amblyomma americanum) and culture in an 115. Kelly P, Lucas H, Beati L, Yowell C, Mahan S, Dame J. 2010. Rickettsia Anopheles gambiae mosquito cell line. Ticks Tick Borne Dis. 3:38–42.

October 2013 Volume 26 Number 4 cmr.asm.org 691 Parola et al.

135. Stromdahl EY, Vince MA, Billingsley PM, Dobbs NA, Williamson PC. Mattar S, Valbuena G. 2011. Outbreak of Rocky Mountain spotted fever 2008. Rickettsia amblyommii infecting Amblyomma americanum larvae. in Cordoba, Colombia. Mem. Inst. Oswaldo Cruz 106:117–118. Vector Borne Zoonotic Dis. 8:15–24. 155. Labruna MB, Kamakura O, Moraes-Filho J, Horta MC, Pacheco RC. 136. Castellaw AH, Showers J, Goddard J, Chenney EF, Varela-Stokes AS. 2009. Rocky Mountain spotted fever in dogs, Brazil. Emerg. Infect. Dis. 2010. Detection of vector-borne agents in lone star ticks, Amblyomma 15:458–460. americanum (Acari: Ixodidae), from Mississippi. J. Med. Entomol. 47: 156. de Sa Del Fiol F, Junqueira FM, da Rocha MCP, de Toledo MI, 473–476. Barberato Filho S. 2010. A febre maculosa no Brasil. Rev. Panam. Salud 137. Apperson CS, Engber B, Nicholson WL, Mead DG, Engel J, Yabsley Publica 27:461–466. MJ, Dail K, Johnson J, Watson DW. 2008. Tick-borne diseases in North 157. Horta MC, Labruna MB, Pinter A, Linardi PM, Schumaker TT. 2007. Carolina: is “Rickettsia amblyommii” a possible cause of rickettsiosis Rickettsia infection in five areas of the state of Sao Paulo, Brazil. Mem. reported as Rocky Mountain spotted fever? Vector Borne Zoonotic Dis. Inst. Oswaldo Cruz 102:793–801. 8:597–606. 158. Guglielmone AA, Beati L, Barros-Battesti DM, Labruna MB, Nava S, 138. Hun L, Troyo A, Taylor L, Barbieri AM, Labruna MB. 2011. First Venzal JM, Mangold AJ, Szabo MP, Martins JR, Gonzalez-Acuna D, report of the isolation and molecular characterization of Rickettsia am- Estrada-Pena A. 2006. Ticks (Ixodidae) on humans in South America. blyommii and Rickettsia felis in Central America. Vector Borne Zoonotic Exp. Appl. Acarol. 40:83–100. Dis. 11:1395–1397. 159. Labruna MB. 2009. Ecology of rickettsia in South America. Ann. N. Y. 139. Bermudez CS, Zaldivar AY, Spolidorio MG, Moraes-Filho J, Miranda Acad. Sci. 1166:156–166. RJ, Caballero CM, Mendoza Y, Labruna MB. 2011. Rickettsial infection 160. Pinter A, Labruna MB. 2006. Isolation of Rickettsia rickettsii and Rick- in domestic mammals and their ectoparasites in El Valle de Anton, Cocle, ettsia bellii in cell culture from the tick Amblyomma aureolatum in Brazil. Panama. Vet. Parasitol. 177:134–138. Ann. N. Y. Acad. Sci. 1078:523–529. 140. Eremeeva ME, Karpathy SE, Levin ML, Caballero CM, Bermudez S, 161. Katz G, Neves VLFC, Angerami RN, Nascimento EMM, Colombo S. Dasch GA, Motta JA. 2009. Spotted fever rickettsiae, Ehrlichia and 2009. Statistics and epidemiology of Brazilian spotted fever in São Paulo, Anaplasma, in ticks from peridomestic environments in Panama. Clin. Brazil. Bol. Epidemiol. Paulista 6:4–13. Microbiol. Infect. 15(Suppl 2):12–14. 162. Ogrzewalska M, Saraiva DG, Moraes-Filho J, Martins TF, Costa FB, 141. Billeter SA, Blanton HL, Little SE, Levy MG, Breitschwerdt EB. 2007. Pinter A, Labruna MB. 2012. Epidemiology of Brazilian spotted fever in Detection of Rickettsia amblyommii in association with a tick bite rash. the Atlantic Forest, state of Sao Paulo, Brazil. Parasitology 139:1283– Vector Borne Zoonotic Dis. 7:607–610. 1300. 142. Nicholson WL, Masters E, Wormser GP. 2009. Preliminary serologic 163. Labruna MB, Ogrzewalska M, Martins TF, Pinter A, Horta MC. 2008. investigation of ‘Rickettsia amblyommii ’ in the aetiology of Southern tick Comparative susceptibility of larval stages of Amblyomma aureolatum, associated rash illness (STARI). Clin. Microbiol. Infect. 15(Suppl 2):235– Amblyomma cajennense, and Rhipicephalus sanguineus to infection by 236. Rickettsia rickettsii. J. Med. Entomol. 45:1156–1159. 143. Jiang J, Stromdahl EY, Richards AL. 2012. Detection of Rickettsia 164. Moraes-Filho J, Pinter A, Pacheco RC, Gutmann TB, Barbosa SO, parkeri and Candidatus Rickettsia andeanae in Amblyomma maculatum Gonzales MA, Muraro MA, Cecilio SR, Labruna MB. 2009. New Gulf Coast ticks collected from humans in the United States. Vector epidemiological data on Brazilian spotted fever in an endemic area of the Borne Zoonotic Dis. 12:175–182. state of Sao Paulo, Brazil. Vector Borne Zoonotic Dis. 9:73–78. 144. Luce-Fedrow A, Wright C, Gaff HD, Sonenshine DE, Hynes WL, 165. Cunha NC, Fonseca AH, Rezende J, Rozental T, Favacho ARM, Richards AL. 2012. In vitro propagation of Candidatus Rickettsia ande- Barreira JD, Massard CL, Lemos ERS. 2009. First identification of anae isolated from Amblyomma maculatum. FEMS Immunol. Med. Mi- natural infection of Rickettsia rickettsii in the Rhipicephalus sanguineus crobiol. 64:74–81. tick, in the State of Rio de Janeiro. Pesqui. Vet. Bras. 29:105–108. 145. Moreno CX, Moy F, Daniels TJ, Godfrey HP, Cabello FC. 2006. 166. Gehrke FS, Gazeta GS, Souza ER, Ribeiro A, Marrelli MT, Schumaker Molecular analysis of microbial communities identified in different de- TT. 2009. Rickettsia rickettsii, Rickettsia felis and Rickettsia sp. TwKM03 velopmental stages of Ixodes scapularis ticks from Westchester and Dutchess Counties, New York. Environ. Microbiol. 8:761–772. infecting Rhipicephalus sanguineus and Ctenocephalides felis collected 146. Rounds MA, Crowder CD, Matthews HE, Philipson CA, Scoles GA, from dogs in a Brazilian spotted fever focus in the State of Rio De Janeiro/ Ecker DJ, Schutzer SE, Eshoo MW. 2012. Identification of endosymbi- Brazil. Clin. Microbiol. Infect. 15(Suppl 2):267–268. onts in ticks by broad-range polymerase chain reaction and electrospray 167. de Almeida RF, Garcia MV, Cunha RC, Matias J, Araujo e Silva E, de ionization mass spectrometry. J. Med. Entomol. 49:843–850. Fatima Cepa Matos M, Andreotti R. 2013. Ixodid fauna and zoonotic 147. Phan JN, Lu CR, Bender WG, Smoak RM, Zhong J, III. 2011. Molec- agents in ticks from dogs: first report of Rickettsia rickettsii in Rhipiceph- ular detection and identification of Rickettsia species in Ixodes pacificus in alus sanguineus in the state of Mato Grosso do Sul, mid-western Brazil. California. Vector Borne Zoonotic Dis. 11:957–961. Exp. Appl. Acarol. 60:63–72. 148. Zemtsova GE, Gleim E, Yabsley MJ, Conner LM, Mann T, Brown MD, 168. Venzal JM, Estrada-Pena A, Portillo A, Mangold AJ, Castro O, De Wendland L, Levin ML. 2012. Detection of a novel spotted fever group Souza CG, Felix ML, Perez-Martinez L, Santibanez S, Oteo JA. 2012. Rickettsia in the gophertortoise tick. J. Med. Entomol. 49:783–786. Rickettsia parkeri: a rickettsial pathogen transmitted by ticks in endemic 149. Loftis AD, Gill JS, Schriefer ME, Levin ML, Eremeeva ME, Gilchrist areas for spotted fever rickettsiosis in southern Uruguay. Rev. Inst. Med. MJ, Dasch GA. 2005. Detection of Rickettsia, Borrelia, and Bartonella in Trop. Sao Paulo 54:131–134. Carios kelleyi (Acari: Argasidae). J. Med. Entomol. 42:473–480. 169. Silveira I, Pacheco RC, Szabo MP, Ramos HG, Labruna MB. 2007. 150. Angerami RN, Resende MR, Feltrin AF, Katz G, Nascimento EM, Rickettsia parkeri in Brazil. Emerg. Infect. Dis. 13:1111–1113. Stucchi RS, Silva LJ. 2006. Brazilian spotted fever: a case series from an 170. Nava S, Elshenawy Y, Eremeeva ME, Sumner JW, Mastropaolo M, endemic area in southeastern Brazil: clinical aspects. Ann. N. Y. Acad. Paddock CD. 2008. Rickettsia parkeri in Argentina. Emerg. Infect. Dis. Sci. 1078:252–254. 14:1894–1897. 151. Angerami RN, da Silva AM, Nascimento EM, Colombo S, Wada MY, 171. Romer Y, Seijo AC, Crudo F, Nicholson WL, Varela-Stokes A, Lash dos Santos FC, Mancini DM, de Oliveira RC, Katz G, Martins EC, da RR, Paddock CD. 2011. Rickettsia parkeri rickettsiosis, Argentina. Silva LJ. 2009. Brazilian spotted fever: two faces of a same disease? A Emerg. Infect. Dis. 17:1169–1173. comparative study of clinical aspects between an old and a new endemic 172. Conti-Diaz IA, Moraes-Filho J, Pacheco RC, Labruna MB. 2009. area in Brazil. Clin. Microbiol. Infect. 15(Suppl 2):207–208. Serological evidence of Rickettsia parkeri as the etiological agent of rick- 152. Hidalgo M, Orejuela L, Fuya P, Carrillo P, Hernandez J, Parra E, Keng ettsiosis in Uruguay. Rev. Inst. Med. Trop. Sao Paulo 51:337–339. C, Small M, Olano JP, Bouyer D, Castaneda E, Walker D, Valbuena G. 173. Cicuttin GL, Rodríguez VM, Jado I, Anda P. 2004. Primera detección 2007. Rocky Mountain spotted fever, Colombia. Emerg. Infect. Dis. 13: de Rickettsia massiliae en la Ciudad de Buenos Aires. Resultados prelim- 1058–1060. inares. Rev. Argent. 1:8–10. 153. Paddock CD, Fernandez S, Echenique GA, Sumner JW, Reeves WK, 174. Garcia-Garcia JC, Portillo A, Nunez MJ, Santibanez S, Castro B, Oteo Zaki SR, Remondegui CE. 2008. Rocky Mountain spotted fever in Ar- JA. 2010. A patient from Argentina infected with Rickettsia massiliae. gentina. Am. J. Trop. Med. Hyg. 78:687–692. Am. J. Trop. Med. Hyg. 82:691–692. 154. Hidalgo M, Miranda J, Heredia D, Zambrano P, Vesga JF, Lizarazo D, 175. Moraes-Filho J, Marcili A, Nieri-Bastos FA, Richtzenhain LJ, Labruna

692 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

MB. 2011. Genetic analysis of ticks belonging to the Rhipicephalus san- Peru: Candidatus Rickettsia andeanae. Ann. N. Y. Acad. Sci. 1063:337– guineus group in Latin America. Acta Trop. 117:51–55. 342. 176. Nava S, Mastropaolo M, Venzal JM, Mangold AJ, Guglielmone AA. 195. Pacheco RC, Moraes-Filho J, Nava S, Brandao PE, Richtzenhain LJ, 2012. Mitochondrial DNA analysis of Rhipicephalus sanguineus sensu Labruna MB. 2007. Detection of a novel spotted fever group rickettsia in lato (Acari: Ixodidae) in the Southern Cone of South America. Vet. Para- Amblyomma parvum ticks (Acari: Ixodidae) from Argentina. Exp. Appl. sitol. 190:547–555. Acarol. 43:63–71. 177. Parola P, Socolovschi C, Jeanjean L, Bitam I, Fournier PE, Sotto A, 196. Tomassone L, Nunez P, Ceballos LA, Gurtler RE, Kitron U, Farber M. Labauge P, Raoult D. 2008. Warmer weather linked to tick attack and 2010. Detection of “Candidatus Rickettsia sp. strain Argentina” and Rick- emergence of severe rickettsioses. PLoS Negl. Trop. Dis. 2:e338. doi:10 ettsia bellii in Amblyomma ticks (Acari: Ixodidae) from Northern Argen- .1371/journal.pntd.0000338. tina. Exp. Appl. Acarol. 52:93–100. 178. Spolidorio MG, Labruna MB, Mantovani E, Brandao PE, Richtzen- 197. Abarca K, Lopez J, Acosta-Jamett G, Lepe P, Soares JF, Labruna MB. hain LJ, Yoshinari NH. 2010. Novel spotted fever group rickettsiosis, 2012. A third Amblyomma species and the first tick-borne rickettsia in Brazil. Emerg. Infect. Dis. 16:521–523. Chile. J. Med. Entomol. 49:219–222. 179. Silva N, Eremeeva ME, Rozental T, Ribeiro GS, Paddock CD, Ramos 198. Ogrzewalska M, Pacheco RC, Uezu A, Richtzenhain LJ, Ferreira F, EA, Favacho AR, Reis MG, Dasch GA, de Lemos ER, Ko AI. 2011. Labruna MB. 2009. Rickettsial infection in Amblyomma nodosum ticks Eschar-associated spotted fever rickettsiosis, Bahia, Brazil. Emerg. Infect. (Acari: Ixodidae) from Brazil. Ann. Trop. Med. Parasitol. 103:413–425. Dis. 17:275–278. 199. Almeida RF, Garcia MV, Cunha RC, Matias J, Labruna MB, Andreotti 180. Sabatini GS, Pinter A, Nieri-Bastos FA, Marcili A, Labruna MB. 2010. R. 2013. The first report of Rickettsia spp. in Amblyomma nodosum in the Survey of ticks (Acari: Ixodidae) and their rickettsia in an Atlantic rain State of Mato Grosso do Sul, Brazil. Ticks Tick Borne Dis. 4:156–159. forest reserve in the State of Sao Paulo, Brazil. J. Med. Entomol. 47:913– 200. Pacheco RC, Arzua M, Nieri-Bastos FA, Moraes-Filho J, Marcili A, 916. Richtzenhain LJ, Barros-Battesti DM, Labruna MB. 2012. Rickettsial 181. Medeiros AP, Souza AP, Moura AB, Lavina MS, Bellato V, Sartor AA, infection in ticks (Acari: Ixodidae) collected on birds in southern Brazil. Nieri-Bastos FA, Richtzenhain LJ, Labruna MB. 2011. Spotted fever J. Med. Entomol. 49:710–716. group Rickettsia infecting ticks (Acari: Ixodidae) in the state of Santa 201. Guedes E, Leite RC, Pacheco RC, Silveira I, Labruna MB. 2011. Catarina, Brazil. Mem. Inst. Oswaldo Cruz 106:926–930. Rickettsia species infecting Amblyomma ticks from an area endemic for 182. Labruna MB, Camargo LM, Camargo EP, Walker DH. 2005. Detection Brazilian spotted fever in Brazil. Rev. Bras. Parasitol. Vet. 20:308–311. of a spotted fever group Rickettsia in the tick Haemaphysalis juxtakochi in 202. Almeida AP, Cunha LM, Bello AC, da Cunha AP, Domingues LN, Rondonia, Brazil. Vet. Parasitol. 127:169–174. Leite RC, Labruna MB. 2011. A novel Rickettsia infecting Amblyomma 183. Labruna MB, Pacheco RC, Richtzenhain LJ, Szabo MP. 2007. Isolation dubitatum ticks in Brazil. Ticks Tick Borne Dis. 2:209–212. of Rickettsia rhipicephali and Rickettsia bellii from Haemaphysalis juxta- 203. Spolidorio MG, Andreoli GS, Martins TF, Brandao PE, Labruna MB. kochi ticks in the state of Sao Paulo, Brazil. Appl. Environ. Microbiol. 2012. Rickettsial infection in ticks collected from road-killed wild ani- 73:869–873. mals in Rio de Janeiro, Brazil. J. Med. Entomol. 49:1510–1514. 204. Miranda J, Portillo A, Oteo JA, Mattar S. 2012. Rickettsia sp. strain 184. Labruna MB, Horta MC, Aguiar DM, Cavalcante GT, Pinter A, Gen- colombianensi (Rickettsiales: Rickettsiaceae): a new proposed Rickettsia nari SM, Camargo LM. 2007. Prevalence of Rickettsia infection in dogs detected in Amblyomma dissimile (Acari: Ixodidae) from iguanas and from the urban and rural areas of Monte Negro municipality, western free-living larvae ticks from vegetation. J. Med. Entomol. 49:960–965. Amazon, Brazil. Vector Borne Zoonotic Dis. 7:249–255. 205. Tomassone L, Conte V, Parrilla G, De Meneghi D. 2010. Rickettsia 185. Labruna MB, Pacheco RC, Nava S, Brandao PE, Richtzenhain LJ, infection in dogs and Rickettsia parkeri in Amblyomma tigrinum ticks, Guglielmone AA. 2007. Infection by Rickettsia bellii and Candidatus Cochabamba Department, Bolivia. Vector Borne Zoonotic Dis. 10:953– “Rickettsia amblyommii”inAmblyomma neumanni ticks from Argentina. 958. Microb. Ecol. 54:126–133. 206. Parola P, Socolovschi C, Raoult D. 2009. Deciphering the relationships 186. Ogrzewalska M, Literak I, Cardenas-Callirgos JM, Capek M, Labruna between Rickettsia conorii conorii and Rhipicephalus sanguineus in the MB. 2012. Rickettsia bellii in ticks Amblyomma varium Koch, 1844, from ecology and epidemiology of Mediterranean spotted fever. Ann. N. Y. birds in Peru. Ticks Tick Borne Dis. 3:254–256. Acad. Sci. 1166:49–54. 187. Pacheco RC, Horta MC, Moraes-Filho J, Ataliba AC, Pinter A, 207. Marquez FJ, Rodriguez-Liebana JJ, Soriguer RC, Muniain MA, Berna- Labruna MB. 2007. Rickettsial infection in capybaras (Hydrochoerus beu-Wittel M, Caruz A, Contreras-Chova F. 2008. Spotted fever group hydrochaeris) from Sao Paulo, Brazil: serological evidence for infection Rickettsia in brown dog ticks Rhipicephalus sanguineus in southwestern by Rickettsia bellii and Rickettsia parkeri. Biomedica 27:364–371. Spain. Parasitol. Res. 103:119–122. 188. Pacheco RC, Moraes-Filho J, Marcili A, Richtzenhain LJ, Szabo MP, 208. Fernandez-Soto P, Perez-Sanchez R, Alamo-Sanz R, Encinas-Grandes Catroxo MH, Bouyer DH, Labruna MB. 2011. Rickettsia monteiroi sp. A. 2006. Spotted fever group rickettsiae in ticks feeding on humans in nov., infecting the tick Amblyomma incisum in Brazil. Appl. Environ. northwestern Spain: is Rickettsia conorii vanishing? Ann. N. Y. Acad. Sci. Microbiol. 77:5207–5211. 1078:331–333. 189. Labruna MB, Mattar S, Nava S, Bermudez S, Venzal JM, Dolz G, 209. Alexandre N, Santos AS, Bacellar F, Boinas FJ, Nuncio MS, de Sousa Abarca K, Romero L, de Sousa R, Oteo J, Zavala-Castro J. 2011. R. 2011. Detection of Rickettsia conorii strains in Portuguese dogs (Canis Rickettsioses in Latin America, Caribbean, Spain and Portugal. Rev. familiaris). Ticks Tick Borne Dis. 2:119–122. MVZ Cordoba 16:2435–2457. 210. Solano-Gallego L, Kidd L, Trotta M, Di Marco M, Caldin M, Fur- 190. Ogrzewalska M, Uezu A, Labruna MB. 2010. Ticks (Acari: Ixodidae) lanello T, Breitschwerdt E. 2006. Febrile illness associated with Rickett- infesting wild birds in the eastern Amazon, northern Brazil, with notes sia conorii infection in dogs from Sicily. Emerg. Infect. Dis. 12:1985– on rickettsial infection in ticks. Parasitol. Res. 106:809–816. 1988. 191. Parola P, Matsumoto K, Socolovschi C, Parzy D, Raoult D. 2007. A 211. Pennisi MG, Capri A, Solano-Gallego L, Lombardo G, Torina A, tick-borne rickettsia of the spotted-fever group, similar to Rickettsia am- Masucci M. 2012. Prevalence of antibodies against Rickettsia conorii, blyommii, in French Guyana. Ann. Trop. Med. Parasitol. 101:185–188. Babesia canis, Ehrlichia canis, and Anaplasma phagocytophilum antigens 192. Ogrzewalska M, Pacheco RC, Uezu A, Ferreira F, Labruna MB. 2008. in dogs from the Stretto di Messina area (Italy). Ticks Tick Borne Dis. Ticks (Acari: Ixodidae) infesting wild birds in an Atlantic forest area in 3:315–318. the state of Sao Paulo, Brazil, with isolation of rickettsia from the tick 212. Bitam I, Parola P, Matsumoto K, Rolain JM, Baziz B, Boubidi SC, Amblyomma longirostre. J. Med. Entomol. 45:770–774. Harrat Z, Belkaid M, Raoult D. 2006. First molecular detection of R. 193. Melo AL, Martins TF, Horta MC, Moraes-Filho J, Pacheco RC, conorii, R. aeschlimannii, and R. massiliae in ticks from Algeria. Ann. Labruna MB, Aguiar DM. 2011. Seroprevalence and risk factors to N. Y. Acad. Sci. 1078:368–372. Ehrlichia spp. and Rickettsia spp. in dogs from the Pantanal Region of 213. Baltadzhiev IG, Popivanova NI. 2012. Some epidemiological features of Mato Grosso State, Brazil. Ticks Tick Borne Dis. 2:213–218. the Mediterranean spotted fever re-emerging in Bulgaria. Folia Med. 194. Jiang J, Blair PJ, Felices V, Moron C, Cespedes M, Anaya E, Schoeler (Plovdiv.) 54:36–43. GB, Sumner JW, Olson JG, Richards AL. 2005. Phylogenetic analysis of 214. Rovery C, Raoult D. 2008. Mediterranean spotted fever. Infect. Dis. a novel molecular isolate of spotted fever group rickettsiae from northern Clin. North Am. 22:515–530.

October 2013 Volume 26 Number 4 cmr.asm.org 693 Parola et al.

215. Rovery C, Brouqui P, Raoult D. 2008. Questions on Mediterranean 235. Leone S, De Marco M, Ghirga P, Nicastri E, Lazzari R, Narciso P. spotted fever a century after its discovery. Emerg. Infect. Dis. 14:1360– 2008. Retinopathy in Rickettsia conorii infection: case report in an immu- 1367. nocompetent host. Infection 36:384–386. 216. de Sousa R, Luz T, Parreira P, Santos-Silva M, Bacellar F. 2006. 236. Kuloglu F, Rolain JM, Akata F, Eroglu C, Celik AD, Parola P. 2012. and climate variability. Ann. N. Y. Acad. Sci. 1078: Mediterranean spotted fever in the Trakya region of Turkey. Ticks Tick 162–169. Borne Dis. 3:298–304. 217. Vescio MF, Piras MA, Ciccozzi M, Carai A, Farchi F, Maroli M, Mura 237. Tsiachris D, Deutsch M, Vassilopoulos D, Zafiropoulou R, Archiman- MS, Rezza G. 2008. Socio-demographic and climatic factors as correlates dritis AJ. 2008. Sensorineural hearing loss complicating severe rickettsial of Mediterranean spotted fever (MSF) in northern Sardinia. Am. J. Trop. diseases: report of two cases. J. Infect. 56:74–76. Med. Hyg. 78:318–320. 238. Caroleo S, Longo C, Pirritano D, Nistico R, Valentino P, Iocco M, 218. Samardzic S, Marinkovic T, Marinkovic D, Djuricic B, Ristanovic E, Santangelo E, Amantea B. 2007. A case of acute quadriplegia compli- Simovic T, Lako B, Vukov B, Bozovic B, Gligic A. 2008. Prevalence of cating Mediterranean spotted fever. Clin. Neurol. Neurosurg. 109:463– antibodies to rickettsiae in different regions of Serbia. Vector Borne Zoo- 465. notic Dis. 8:219–224. 239. Tzavella K, Chatzizisis YS, Vakali A, Mandraveli K, Zioutas D, Alex- 219. Serban R, Pistol A, Negut M, Cucuiu R. 2009. Rickettsia conorii infec- iou-Daniel S. 2006. Severe case of Mediterranean spotted fever in Greece tion in Romania, 2000-2008. Bacteriol. Virusol. Parazitol. Epidemiol. with predominantly neurological features. J. Med. Microbiol. 55:341– 54:177–183. (In Romanian.) 343. 220. Kovacova E, Sekeyova Z, Travnicek M, Bhide MR, Mardzinova S, 240. Botelho-Nevers E, Foucault C, Lepidi H, Brouqui P. 2005. Cerebral Curlik J, Spanelova D. 2006. Monitoring of humans and animals for the infarction: an unusual complication of Mediterranean spotted fever. Eur. presence of various Rickettsiae and Coxiella burnetii by serological meth- J. Intern. Med. 16:525–527. ods. Ann. N. Y. Acad. Sci. 1078:587–589. 241. Spengos K, Stouraitis G, Voumvourakis K, Zambelis T, Karandreas N. 221. Tonna I, Mallia AC, Piscopo T, Cuschieri P, Fenollar F, Raoult D. 2005. Motor and sensory polyneuritis with distal conduction failure as 2006. Characterisation of rickettsial diseases in a hospital-based popula- uncommon complication of an acute Rickettsia conorii infection. J. Neu- tion in Malta. J. Infect. 53:394–402. rol. Sci. 234:113–116. 222. Cinco M, Luzzati R, Mascioli M, Floris R, Brouqui P. 2006. Serological 242. Rombola F. 2011. Mediterranean spotted fever presenting as an acute evidence of Rickettsia infections in forestry rangers in north-eastern Italy. pancreatitis. Acta Gastroenterol. Belg. 74:91–92. Clin. Microbiol. Infect. 12:493–495. 243. Tikare NV, Shahapur PR, Bidari LH, Mantur BG. 2010. Rickettsial 223. Bolanos-Rivero M, Santana-Rodriguez E, Angel-Moreno A, Hernan- meningoencephalitis in a child—a case report. J. Trop. Pediatr. 56:198– dez-Cabrera M, Liminana-Canal JM, Carranza-Rodriguez C, Martin- 200. Sanchez AM, Perez-Arellano JL. 2011. Seroprevalence of Rickettsia typhi 244. Schmulewitz L, Moumile K, Patey-Mariaud de Serre N, Poiree S, and Rickettsia conorii infections in the Canary Islands (Spain). Int. J. Gouin E, Mechai F, Cocard V, Mamzer-Bruneel MF, Abachin E, Infect. Dis. 15:e481–e485. doi:10.1016/j.ijid.2011.03.019. Berche P, Lortholary O, Lecuit M. 2008. Splenic rupture and malignant 224. Lledo L, Gonzalez R, Gegundez MI, Beltran M, Saz JV. 2009. Epide- Mediterranean spotted fever. Emerg. Infect. Dis. 14:995–997. miological study of rickettsial infections in patients with hypertransa- 245. Montasser DI, Zajjari Y, Alayoud A, Bahadi A, Aatif T, Hassani K, minemia in Madrid (Spain). Int. J. Environ. Res. Public Health 6:2526– Hamzi A, Allam M, Benyahia M, Oualim Z. 2011. Acute renal failure as 2533. a complication of Mediterranean spotted fever. Nephrol. Ther. 7:245– 225. Bernabeu-Wittel M, del Toro MD, Nogueras MM, Muniain MA, 247. (In French.) Cardenosa N, Marquez FJ, Segura F, Pachon J. 2006. Seroepidemio- 246. Perez-De Pedro I, Macias-Vega IN, Miranda-Candon I, Camps-Garcia logical study of Rickettsia felis, Rickettsia typhi, and Rickettsia conorii in- MT. 2008. Severe Rickettsia conorii infection associated with he- fection among the population of southern Spain. Eur. J. Clin. Microbiol. mophagocytic syndrome. Enferm. Infecc. Microbiol. Clin. 26:597–598. Infect. Dis. 25:375–381. (In French.) 226. Sousa R, Franca A, Doria NS, Belo A, Amaro M, Abreu T, Pocas J, 247. Papa A, Dalla V, Petala A, Maltezou HC, Maltezos E. 2010. Fatal Proenca P, Vaz J, Torgal J, Bacellar F, Ismail N, Walker DH. 2008. Mediterranean spotted fever in Greece. Clin. Microbiol. Infect. 16:589– Host- and microbe-related risk factors for and pathophysiology of fatal 592. Rickettsia conorii infection in Portuguese patients. J. Infect. Dis. 198:576– 248. Bechah Y, Socolovschi C, Raoult D. 2011. Identification of rickettsial 585. infections by using cutaneous swab specimens and PCR. Emerg. Infect. 227. Germanakis A, Psaroulaki A, Gikas A, Tselentis Y. 2006. Mediterra- Dis. 17:83–86. nean spotted fever in Crete, Greece: clinical and therapeutic data of 15 249. de Sousa R, Santos-Silva M, Santos AS, Barros SC, Torgal J, Walker consecutive patients. Ann. N. Y. Acad. Sci. 1078:263–269. DH, Bacellar F. 2007. Rickettsia conorii israeli tick typhus strain isolated 228. Colomba C, Saporito L, Polara VF, Rubino R, Titone L. 2006. Medi- from Rhipicephalus sanguineus ticks in Portugal. Vector Borne Zoonotic terranean spotted fever: clinical and laboratory characteristics of 415 Dis. 7:444–447. Sicilian children. BMC Infect. Dis. 6:60. doi:10.1186/1471-2334-6-60. 250. Giammanco GM, Di Rosa S, Ammatuna P, Mansueto P, Micalizzi A, 229. Kuloglu F, Rolain JM, Aydoslu B, Akata F, Tugrul M, Raoult D. 2006. Vitale G. 2005. Continous [sic] alert for rickettsiosis in Sicily: molecular Prospective evaluation of rickettsioses in the Trakya (European) region characterization of Rickettsia sp. obtained from ticks and human beings of Turkey and atypic presentations of Rickettsia conorii. Ann. N. Y. Acad. (1986-2001). New Microbiol. 28:377–379. Sci. 1078:173–175. 251. Boillat N, Genton B, D’Acremont V, Raoult D, Greub G. 2008. Fatal 230. Bartolome J, Lorente S, Hernandez-Perez N, Martinez-Alfaro E, case of Israeli spotted fever after Mediterranean cruise. Emerg. Infect. Marin-Ors A, Crespo MD. 2005. Clinical and epidemiological study of Dis. 14:1944–1946. spotted fever group rickettsiosis in Albacete, Spain. Enferm. Infecc. Mi- 252. Chai JT, Eremeeva ME, Borland CD, Karas JA. 2008. Fatal Israeli crobiol. Clin. 23:194–196. (In Spanish.) spotted fever in a UK traveler to South Portugal. J. Travel Med. 15:122– 231. Cascio A, Maggio MC, Cardella F, Zangara V, Accomando S, Costa A, 123. Iaria C, Mansueto P, Giordano S. 2011. Coronary involvement in 253. Giammanco GM, Vitale G, Mansueto S, Capra G, Caleca MP, Amma- Mediterranean spotted fever. New Microbiol. 34:421–424. tuna P. 2005. Presence of Rickettsia conorii subsp. israelensis, the caus- 232. Ben Mansour N, Barakett N, Hajlaoui N, Haggui A, Filali T, Dahmen ative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retro- R, Fehri W, Haouala H. 2011. Acute myocarditis complicating Medi- spective study. J. Clin. Microbiol. 43:6027–6031. terranean spotted fever. A case report. Ann. Cardiol. Angeiol. (Paris) 254. Renvoise A, Delaunay P, Blanchouin E, Cannavo I, Cua E, Socolovschi doi:10.1016/j.ancard.2011.05.003. (In French.) C, Parola P, Raoult D. 2012. Urban family cluster of spotted fever 233. Colomba C, Saporito L, Colletti P, Mazzola G, Rubino R, Pampinella rickettsiosis linked to Rhipicephalus sanguineus infected with Rickettsia D, Titone L. 2008. Atrial fibrillation in Mediterranean spotted fever. J. conorii subsp. caspia and Rickettsia massiliae. Ticks Tick Borne Dis. Med. Microbiol. 57:1424–1426. 3:389–392. 234. Agahan AL, Torres J, Fuentes-Paez G, Martinez-Osorio H, Orduna A, 255. Pokrovsky VI, Ugleva SV, Shabalina SV. 2011. Comparative character- Calonge M. 2011. Intraocular inflammation as the main manifestation istics of transmissive fevers in the territory of Astrakhan region (clini- of Rickettsia conorii infection. Clin. Ophthalmol. 5:1401–1407. coepidemiological evidence). Ter. Arkh. 83(11):55–59. (In Russian.)

694 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

256. Maleev VV, Galimzianov K, Lazareva EN, Poliakova AM, Astrina OS, Rickettsia sibirica subsp. mongolitimonae infection and retinal vasculitis. Kudriavtsev VA, Arshba TE. 2009. Hemostatic disorders and their im- Emerg. Infect. Dis. 14:683–684. plication in the pathogenesis of Astrakhan rickettsial fever. Ter. Arkh. 277. Gilot B, Laforge ML, Pichot J, Raoult D. 1990. Relationships between 81(11):32–35. (In Russian.) the Rhipicephalus sanguineus complex ecology and Mediterranean spot- 257. Torina A, Fernandez de Mera IG, Alongi A, Mangold AJ, Blanda V, ted fever epidemiology in France. Eur. J. Epidemiol. 6:357–362. Scarlata F, Di Marco V, de la Fuente J. 2012. Rickettsia conorii Indian 278. Walker AR, Bouattour A, Camicas J-L, Estrada-Peña A, Horak IG, tick typhus strain and R. slovaca in humans, Sicily. Emerg. Infect. Dis. Latif AA, Pegram RG, Reston PM. 2003. Ticks of domestic animals in 18:1008–1010. Africa. A guide to identification of species. Bioscience Reports, Edin- 258. Chochlakis D, Ioannou I, Sandalakis V, Dimitriou T, Kassinis N, burgh, United Kingdom. Papadopoulos B, Tselentis Y, Psaroulaki A. 2012. Spotted fever group 279. Angelakis E, Pulcini C, Waton J, Imbert P, Socolovschi C, Edouard S, rickettsiae in ticks in Cyprus. Microb. Ecol. 63:314–323. Dellamonica P, Raoult D. 2010. Scalp eschar and neck lymphadenopa- 259. Socolovschi C, Reynaud P, Kernif T, Raoult D, Parola P. 2012. Rick- thy caused by after tick bite. Clin. Infect. Dis. 50:549– ettsiae of spotted fever group, Borrelia valaisiana, and Coxiella burnetii in 551. ticks on passerine birds and mammals from the Camargue in the south of 280. Maioli G, Pistone D, Bonilauri P, Pajoro M, Barbieri I, Mulatto P, France. Ticks Tick Borne Dis. 3:355–360. Vicari N, Dottori M. 2012. Ethiological [sic] agents of rickettsiosis and 260. Marie JL, Davoust B, Socolovschi C, Raoult D, Parola P. 2012. Mo- in ticks collected in Emilia-Romagna region (Italy) during lecular detection of rickettsial agents in ticks and fleas collected from a 2008 and 2009. Exp. Appl. Acarol. 57:199–208. European hedgehog (Erinaceus europaeus) in Marseilles, France. Comp. 281. Spitalska E, Stefanidesova K, Kocianova E, Boldis V. 2012. Rickettsia Immunol. Microbiol. Infect. Dis. 35:77–79. slovaca and Rickettsia raoultii in Dermacentor marginatus and Dermacen- 261. Marie JL, Davoust B, Socolovschi C, Mediannikov O, Roqueplo C, tor reticulatus ticks from Slovak Republic. Exp. Appl. Acarol. 57:189– Beaucournu JC, Raoult D, Parola P. 2012. Rickettsiae in arthropods 197. collected from red foxes (Vulpes vulpes) in France. Comp. Immunol. 282. Dobler G, Wolfel R. 2009. Typhus and other rickettsioses: emerging Microbiol. Infect. Dis. 35:59–62. infections in Germany. Dtsch. Arztebl. Int. 106:348–354. 262. Fernandez de Mera IG, Zivkovic Z, Bolanos M, Carranza C, Perez- 283. Milhano N, de Carvalho IL, Alves AS, Arroube S, Soares J, Rodriguez Arellano JL, Gutierrez C, de la Fuente J. 2009. Rickettsia massiliae in the P, Carolino M, Nuncio MS, Piesman J, de Sousa R. 2010. Coinfections Canary Islands. Emerg. Infect. Dis. 15:1869–1870. of Rickettsia slovaca and Rickettsia helvetica with Borrelia lusitaniae in 263. Toledo A, Olmeda AS, Escudero R, Jado I, Valcarcel F, Casado-Nistal ticks collected in a Safari Park, Portugal. Ticks Tick Borne Dis. 1:172– MA, Rodriguez-Vargas M, Gil H, Anda P. 2009. Tick-borne zoonotic 177. bacteria in ticks collected from central Spain. Am. J. Trop. Med. Hyg. 284. Masala G, Chisu V, Satta G, Socolovschi C, Raoult D, Parola P. 2012. 81:67–74. Rickettsia slovaca from Dermacentor marginatus ticks in Sardinia, Italy. 264. Psaroulaki A, Ragiadakou D, Kouris G, Papadopoulos B, Chaniotis B, Ticks Tick Borne Dis. 3:393–395. Tselentis Y. 2006. Ticks, tick-borne rickettsiae, and Coxiella burnetii in 285. Kachrimanidou M, Souliou E, Pavlidou V, Antoniadis A, Papa A. 2010. First detection of Rickettsia slovaca in Greece. Exp. Appl. Acarol. the Greek Island of Cephalonia. Ann. N. Y. Acad. Sci. 1078:389–399. 50:93–96. 265. Tomanovic S, Chochlakis D, Radulovic Z, Milutinovic M, Cakic S, 286. Chmielewski T, Podsiadly E, Karbowiak G, Tylewska-Wierzbanowska Mihaljica D, Tselentis Y, Psaroulaki A. 2013. Analysis of pathogen S. 2009. Rickettsia spp. in ticks, Poland. Emerg. Infect. Dis. 15:486–488. co-occurrence in host-seeking adult hard ticks from Serbia. Exp. Appl. 287. Dobec M, Golubic D, Punda-Polic V, Kaeppeli F, Sievers M. 2009. Acarol. 59:367–376. Rickettsia helvetica in Dermacentor reticulatus ticks. Emerg. Infect. Dis. 266. Trotta M, Nicetto M, Fogliazza A, Montarsi F, Caldin M, Furlanello T, 15:98–100. Solano-Gallego L. 2012. Detection of Leishmania infantum, Babesia 288. Selmi M, Bertolotti L, Tomassone L, Mannelli A. 2008. Rickettsia canis, and rickettsiae in ticks removed from dogs living in Italy. Ticks slovaca in Dermacentor marginatus and tick-borne lymphadenopathy, Tick Borne Dis. 3:294–297. Tuscany, Italy. Emerg. Infect. Dis. 14:817–820. 267. Podsiadly E, Chmielewski T, Karbowiak G, Kedra E, Tylewska- 289. Reye AL, Stegniy V, Mishaeva NP, Velhin S, Hubschen JM, Ignatyev Wierzbanowska S. 2011. The occurrence of spotted fever rickettsioses G, Muller CP. 2013. Prevalence of tick-borne pathogens in Ixodes ricinus and other tick-borne infections in forest workers in Poland. Vector and Dermacentor reticulatus ticks from different geographical locations Borne Zoonotic Dis. 11:985–989. in Belarus. PLoS One 8:e54476. doi:10.1371/journal.pone.0054476. 268. Edouard S, Parola P, Socolovschi C, Davoust B, La Scola B, Raoult D. 290. Jiang J, You BJ, Liu E, Apte A, Yarina TR, Myers TE, Lee JS, Fran- 2013. Clustered cases of Rickettsia sibirica mongolitimonae infection, cesconi SC, O’Guinn ML, Tsertsvadze N, Vephkhvadze N, Babuadze France. Emerg. Infect. Dis. 19:337–338. G, Sidamonidze K, Kokhreidze M, Donduashvili M, Onashvili T, 269. Psaroulaki A, Germanakis A, Gikas A, Scoulica E, Tselentis Y. 2005. Ismayilov A, Agayev N, Aliyev M, Muttalibov N, Richards AL. 2012. Simultaneous detection of “Rickettsia mongolotimonae” in a patient and Development of three quantitative real-time PCR assays for the detection in a tick in Greece. J. Clin. Microbiol. 43:3558–3559. of Rickettsia raoultii, Rickettsia slovaca, and Rickettsia aeschlimannii and 270. de Sousa R, Barata C, Vitorino L, Santos-Silva M, Carrapato C, Torgal their validation with ticks from the country of Georgia and the Republic J, Walker D, Bacellar F. 2006. Rickettsia sibirica isolation from a patient of Azerbaijan. Ticks Tick Borne Dis. 3:327–331. and detection in ticks, Portugal. Emerg. Infect. Dis. 12:1103–1108. 291. Porta FS, Nieto EA, Creus BF, Espin TM, Casanova FJ, Sala IS, Garcia 271. de Sousa R, Duque L, Anes M, Pocas J, Torgal J, Bacellar F, Olano JP, SL, Aguilar JL, Vilaseca MQ. 2008. Tick-borne lymphadenopathy: a Walker DH. 2008. Lymphangitis in a Portuguese patient infected with new infectious disease in children. Pediatr. Infect. Dis. J. 27:618–622. Rickettsia sibirica. Emerg. Infect. Dis. 14:529–530. 292. Parola P, Rovery C, Rolain JM, Brouqui P, Davoust B, Raoult D. 2009. 272. Ibarra V, Portillo A, Palomar AM, Sanz MM, Metola L, Blanco JR, Rickettsia slovaca and R. raoultii in tick-borne rickettsioses. Emerg. In- Oteo JA. 2012. Septic shock in a patient infected with Rickettsia sibirica fect. Dis. 15:1105–1108. mongolitimonae, Spain. Clin. Microbiol. Infect. 18:E283–E285. doi:10 293. Gouriet F, Rolain JM, Raoult D. 2006. Rickettsia slovaca infection, .1111/j.1469-0691.2012.03887.x. France. Emerg. Infect. Dis. 12:521–523. 273. Aguirrebengoa K, Portillo A, Santibanez S, Marin JJ, Montejo M, Oteo 294. Sekeyova Z, Subramanian G, Mediannikov O, Diaz MQ, Nyitray A, JA. 2008. Human Rickettsia sibirica mongolitimonae infection, Spain. Blaskovicova H, Raoult D. 2012. Evaluation of clinical specimens for Emerg. Infect. Dis. 14:528–529. Rickettsia, Bartonella, Borrelia, Coxiella, Anaplasma, Franciscella and 274. Fleta-Asin B, Alonso-Castro L, Jado-Garcia I, Anda-Fernandez P. Diplorickettsia positivity using serological and molecular biology meth- 2011. Detection by polymerase chain reaction of Rickettsia sibirica mon- ods. FEMS Immunol. Med. Microbiol. 64:82–91. golotimonae in the skin biopsy of a rash: a case report. Enferm. Infecc. 295. Ibarra V, Oteo JA, Portillo A, Santibanez S, Blanco JR, Metola L, Eiros Microbiol. Clin. 29:778–779. (In Spanish.) JM, Perez-Martinez L, Sanz M. 2006. Rickettsia slovaca infection: DEB- 275. Ramos JM, Jado I, Padilla S, Masia M, Anda P, Gutierrez F. 2013. ONEL/TIBOLA. Ann. N. Y. Acad. Sci. 1078:206–214. Human infection with Rickettsia sibirica mongolitimonae, Spain, 2007- 296. Switaj K, Chmielewski T, Borkowski P, Tylewska-Wierzbanowska S, 2011. Emerg. Infect. Dis. 19:267–269. Olszynska-Krowicka M. 2012. Spotted fever rickettsiosis caused by Rick- 276. Caron J, Rolain JM, Mura F, Guillot B, Raoult D, Bessis D. 2008. ettsia raoultii—case report. Przegl. Epidemiol. 66:347–350.

October 2013 Volume 26 Number 4 cmr.asm.org 695 Parola et al.

297. Madeddu G, Mancini F, Caddeo A, Ciervo A, Babudieri S, Maida I, Portillo A, Oteo JA. 2012. Role of birds in dispersal of etiologic agents of Fiori ML, Rezza G, Mura MS. 2012. Rickettsia monacensis as cause of tick-borne zoonoses, Spain, 2009. Emerg. Infect. Dis. 18:1188–1191. Mediterranean spotted fever-like illness, Italy. Emerg. Infect. Dis. 18: 318. Socolovschi C, Kernif T, Raoult D, Parola P. 2012. Borrelia, Rickettsia, 702–704. and Ehrlichia species in bat ticks, France, 2010. Emerg. Infect. Dis. 18: 298. Jado I, Oteo JA, Aldamiz M, Gil H, Escudero R, Ibarra V, Portu J, 1966–1975. Portillo A, Lezaun MJ, Garcia-Amil C, Rodriguez-Moreno I, Anda P. 319. Marquez FJ. 2008. Spotted fever group Rickettsia in ticks from south- 2007. Rickettsia monacensis and human disease, Spain. Emerg. Infect. Dis. eastern Spain natural parks. Exp. Appl. Acarol. 45:185–194. 13:1405–1407. 320. Eremeeva ME, Oliveira A, Robinson JB, Ribakova N, Tokarevich NK, 299. Gargili A, Palomar AM, Midilli K, Portillo A, Kar S, Oteo JA. 2012. Dasch GA. 2006. Prevalence of bacterial agents in Ixodes persulcatus ticks Rickettsia species in ticks removed from humans in Istanbul, Turkey. from the Vologda Province of Russia. Ann. N. Y. Acad. Sci. 1078:291– Vector Borne Zoonotic Dis. 12:938–941. 298. 300. Reye AL, Hubschen JM, Sausy A, Muller CP. 2010. Prevalence and 321. Jaaskelainen AE, Tikkakoski T, Uzcategui NY, Alekseev AN, Vaheri A, seasonality of tick-borne pathogens in questing Ixodes ricinus ticks from Vapalahti O. 2006. Siberian subtype tickborne encephalitis virus, Fin- Luxembourg. Appl. Environ. Microbiol. 76:2923–2931. land. Emerg. Infect. Dis. 12:1568–1571. 301. Rymaszewska A, Piotrowski M. 2013. Use of DNA sequences for Rick- 322. Eremeeva ME, Stromdahl EY. 2011. New spotted fever group Rickettsia ettsia identification in Ixodes ricinus ticks: the first detection of Rickettsia in a Rhipicephalus turanicus tick removed from a child in eastern Sicily, monacensis in Poland. Microbes Infect. 15:140–146. Italy. Am. J. Trop. Med. Hyg. 84:99–101. 302. Radulovic Z, Chochlakis D, Tomanovic S, Milutinovic M, Tselentis Y, 323. Elfving K, Olsen B, Bergstrom S, Waldenstrom J, Lundkvist A, Sjost- Psaroulaki A. 2011. First detection of spotted fever group rickettsiae in edt A, Mejlon H, Nilsson K. 2010. Dissemination of spotted fever ticks in Serbia. Vector Borne Zoonotic Dis. 11:111–115. rickettsia agents in Europe by migrating birds. PLoS One 5:e8572. doi:10 303. de Sousa R, Lopes de Carvalho I, Santos AS, Bernardes C, Milhano N, .1371/journal.pone.0008572. Jesus J, Menezes D, Nuncio MS. 2012. Role of the lizard Teira dugesii as 324. Floris R, Yurtman AN, Margoni EF, Mignozzi K, Boemo B, Altobelli a potential host for Ixodes ricinus tick-borne pathogens. Appl. Environ. A, Cinco M. 2008. Detection and identification of Rickettsia species in Microbiol. 78:3767–3769. the northeast of Italy. Vector Borne Zoonotic Dis. 8:777–782. 304. Rumer L, Graser E, Hillebrand T, Talaska T, Dautel H, Mediannikov 325. Socolovschi C, Matsumoto K, Phong HT, Davoust B, Raoult D, Parola O, Roy-Chowdhury P, Sheshukova O, Donoso MO, Niedrig M. 2011. P. 2009. Transmission of Rickettsia sp. DmS1 in the tick, Dermacentor Rickettsia aeschlimannii in Hyalomma marginatum ticks, Germany. marginatus. Clin. Microbiol. Infect. 15(Suppl 2):322–323. Emerg. Infect. Dis. 17:325–326. 326. Portillo A, Ibarra V, Santibanez S, Perez-Martinez L, Blanco JR, Oteo 305. Shpynov S, Rudakov N, Tohkov Y, Matushchenko A, Tarasevich I, JA. 2009. Genetic characterisation of ompA, ompB and gltA genes from Raoult D, Fournier PE. 2009. Detection of Rickettsia aeschlimannii in Candidatus Rickettsia rioja. Clin. Microbiol. Infect. 15(Suppl 2):307–308. Hyalomma marginatum ticks in western Russia. Clin. Microbiol. Infect. 327. Perez-Perez L, Portillo A, Allegue F, Zulaica A, Oteo JA, Caeiro JL, 15(Suppl 2):315–316. Fabeiro JM. 2010. Dermacentor-borne necrosis erythema and lymph- adenopathy (DEBONEL): a case associated with Rickettsia rioja. Acta 306. Mura A, Masala G, Tola S, Satta G, Fois F, Piras P, Rolain JM, Raoult Derm. Venereol. 90:214–215. D, Parola P. 2008. First direct detection of rickettsial pathogens and a 328. Dubska L, Literak I, Kverek P, Roubalova E, Kocianova E, Taragelova new rickettsia, ‘Candidatus Rickettsia barbariae’, in ticks from Sardinia, V. 2012. Tick-borne zoonotic pathogens in ticks feeding on the common Italy. Clin. Microbiol. Infect. 14:1028–1033. nightingale including a novel strain of Rickettsia sp. Ticks Tick Borne Dis. 307. Fernandez-Soto P, Encinas-Grandes A, Perez-Sanchez R. 2003. Rick- 3:265–268. ettsia aeschlimannii in Spain: molecular evidence in Hyalomma mar- 329. Sreter-Lancz Z, Szell Z, Kovacs G, Egyed L, Marialigeti K, Sreter T. ginatum and five other tick species that feed on humans. Emerg. Infect. 2006. Rickettsiae of the spotted-fever group in ixodid ticks from Hun- Dis. 9:889–890. gary: identification of a new genotype (‘Candidatus Rickettsia kotlanii’). 308. Hornok S, Csorgo T, de la Fuente J, Gyuranecz M, Privigyei C, Meli Ann. Trop. Med. Parasitol. 100:229–236. ML, Kreizinger Z, Gonczi E, Fernandez de Mera IG, Hofmann- 330. Graham RI, Mainwaring MC, Du Feu R. 2010. Detection of spotted Lehmann R. 2013. Synanthropic birds associated with high prevalence of fever group Rickettsia spp. from bird ticks in the U.K. Med. Vet. Entomol. tick-borne rickettsiae and with the first detection of Rickettsia aeschli- 24:340–343. mannii in Hungary. Vector Borne Zoonotic Dis. 13:77–83. 331. van Overbeek L, Gassner F, van der Plas CL, Kastelein P, Nunes-da 309. Tomassone L, Grego E, Auricchio D, Iori A, Giannini F, Rambozzi L. Rocha U, Takken W. 2008. Diversity of Ixodes ricinus tick-associated 2013. Lyme borreliosis spirochetes and spotted fever group rickettsiae in bacterial communities from different forests. FEMS Microbiol. Ecol. 66: ixodid ticks from Pianosa Island, Tuscany Archipelago, Italy. Vector 72–84. Borne Zoonotic Dis. 13:84–91. 332. Tijsse-Klasen E, Fonville M, van Overbeek L, Reimerink JH, Sprong H. 310. Kantso B, Svendsen CB, Jensen PM, Vennestrom J, Krogfelt KA. 2010. 2010. Exotic rickettsiae in Ixodes ricinus: fact or artifact? Parasit. Vectors Seasonal and habitat variation in the prevalence of Rickettsia helvetica in 3:54. doi:10.1186/1756-3305-3-54. Ixodes ricinus ticks from Denmark. Ticks Tick Borne Dis. 1:101–103. 333. Kernif T, Socolovschi C, Bitam I, Raoult D, Parola P. 2012. Vector- 311. Sprong H, Wielinga PR, Fonville M, Reusken C, Brandenburg AH, borne rickettsioses in North Africa. Infect. Dis. Clin. North Am. 26:455– Borgsteede F, Gaasenbeek C, van der Giessen JW. 2009. Ixodes 478. ricinus ticks are reservoir hosts for Rickettsia helvetica and potentially 334. Kaabia N, Bellazreg F, Hachfi W, Khalifa M, Ghanouchi N, Bahri F, carry flea-borne Rickettsia species. Parasit. Vectors 2:41. doi:10.1186 Letaief A. 2009. Rickettsial infection in hospitalised patients in central /1756-3305-2-41. Tunisia: report of 119 cases. Clin. Microbiol. Infect. 15(Suppl 2):216– 312. Spitalska E, Literak I, Kocianova E, Taragel’ova V. 2011. The impor- 217. tance of Ixodes arboricola in transmission of Rickettsia spp., Anaplasma 335. Mouffok N, Parola P, Lepidi H, Raoult D. 2009. Mediterranean spotted phagocytophilum, and Borrelia burgdorferi sensu lato in the Czech Repub- fever in Algeria—new trends. Int. J. Infect. Dis. 13:227–235. lic, Central Europe. Vector Borne Zoonotic Dis. 11:1235–1241. 336. Sfar N, Kaabia N, Letaief A, Rolain JM, Parola P, Bouattour A, Raoult 313. Nilsson K. 2009. Septicaemia with Rickettsia helvetica in a patient with D. 2009. First molecular detection of R. conorii subsp. conorii 99 years acute febrile illness, rash and myasthenia. J. Infect. 58:79–82. after the Conor description of Mediterranean spotted fever, in Tunisia. 314. Nilsson K, Elfving K, Pahlson C. 2010. Rickettsia helvetica in patient Clin. Microbiol. Infect. 15(Suppl 2):309–310. with meningitis, Sweden, 2006. Emerg. Infect. Dis. 16:490–492. 337. Boudebouch N, Sarih M, Socolovschi C, Amarouch H, Hassar M, 315. Nilsson K, Wallmenius K, Pahlson C. 2011. Coinfection with Rickettsia Raoult D, Parola P. 2009. Molecular survey for spotted fever group helvetica and herpes simplex virus 2 in a young woman with meningoen- rickettsiae in ticks from Morocco. Clin. Microbiol. Infect. 15(Suppl 2): cephalitis. Case Rep. Infect. Dis. 2011:469194. doi:10.1155/2011/469194. 259–260. 316. Svendsen CB, Milman N, Andersen CB, Rasmussen EM, Thomsen 338. Znazen A, Hammami B, Lahiani D, Ben Jemaa M, Hammami A. 2011. VO, Krogfelt KA. 2011. Is sarcoidosis a rickettsiosis? An archival study. Israeli spotted fever, Tunisia. Emerg. Infect. Dis. 17:1328–1330. Scand. J. Infect. Dis. 43:349–353. 339. Raoult D, Fournier PE, Abboud P, Caron F. 2002. First documented 317. Palomar AM, Santibanez P, Mazuelas D, Roncero L, Santibanez S, human Rickettsia aeschlimannii infection. Emerg. Infect. Dis. 8:748–749.

696 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

340. Mokrani N, Parola P, Tebbal S, Dalichaouche M, Aouati A, Raoult D. 362. Mechai F, Han Y, Gachot B, Consigny PH, Viard JP, Lecuit M, 2008. Rickettsia aeschlimannii infection, Algeria. Emerg. Infect. Dis. 14: Lortholary O. 2009. Pristinamycin for Rickettsia africae infection. J. 1814–1815. Travel Med. 16:136–137. 341. Sarih M, Socolovschi C, Boudebouch N, Hassar M, Raoult D, Parola 363. Consigny PH, Schuett I, Fraitag S, Rolain JM, Buffet P. 2009. Unusual P. 2008. Spotted fever group rickettsiae in ticks, Morocco. Emerg. Infect. location of an inoculation lesion in a traveler with African tick-bite fever Dis. 14:1067–1073. returning from South Africa. J. Travel Med. 16:439–440. 342. Abdel-Shafy S, Allam NA, Mediannikov O, Parola P, Raoult D. 2012. 364. Roch N, Epaulard O, Pelloux I, Pavese P, Brion JP, Raoult D, Maurin Molecular detection of spotted fever group rickettsiae associated with M. 2008. African tick bite fever in elderly patients: 8 cases in French ixodid ticks in Egypt. Vector Borne Zoonotic Dis. 12:346–359. tourists returning from South Africa. Clin. Infect. Dis. 47:e28–e35. doi: 343. Kernif T, Djerbouh A, Mediannikov O, Ayach B, Rolain JM, Raoult D, 10.1086/589868. Parola P, Bitam I. 2012. Rickettsia africae in Hyalomma dromedarii ticks 365. Bouvresse S, Del Giudice P, Franck N, Buffet M, Avril MF, Mondain from sub-Saharan Algeria. Ticks Tick Borne Dis. 3:377–379. V, Rolain JM, Raoult D, Dupin N. 2008. Two cases of cellulitis in the 344. Fournier PE, Gouriet F, Brouqui P, Lucht F, Raoult D. 2005. Lymp- course of African tick bite fever: a fortuitous association? Dermatology hangitis-associated rickettsiosis, a new rickettsiosis caused by Rickettsia 217:140–142. sibirica mongolotimonae: seven new cases and review of the literature. 366. Hochedez P, Canestri A, Guihot A, Brichler S, Bricaire F, Caumes E. Clin. Infect. Dis. 40:1435–1444. 2008. Management of travelers with fever and exanthema, notably den- 345. Socolovschi C, Barbarot S, Lefebvre M, Parola P, Raoult D. 2010. gue and chikungunya infections. Am. J. Trop. Med. Hyg. 78:710–713. Rickettsia sibirica mongolitimonae in traveler from Egypt. Emerg. Infect. 367. Consigny PH, Rolain JM, Mizzi D, Raoult D. 2005. African tick-bite Dis. 16:1495–1496. fever in French travelers. Emerg. Infect. Dis. 11:1804–1806. 346. Kernif T, Messaoudene D, Ouahioune S, Parola P, Raoult D, Bitam I. 368. Schleenvoigt BT, Keller P, Stallmach A, Pletz MW. 2012. African tick 2012. Spotted fever group rickettsiae identified in Dermacentor margin- bite fever—rickettsiosis after holiday in South Africa. Dtsch. Med. atus and Ixodes ricinus ticks in Algeria. Ticks Tick Borne Dis. 3:380–381. Wochenschr. 137:891–893. (In German.) 347. Sfar N, M’ghirbi Y, Letaief A, Parola P, Bouattour A, Raoult D. 2008. 369. Tappe D, Dobler G, Stich A. 2009. Tache noire in African tick bite fever. First report of Rickettsia monacensis and Rickettsia helvetica from Tunisia. Am. J. Trop. Med. Hyg. 81:733–734. Ann. Trop. Med. Parasitol. 102:561–564. 370. Schuster J, Tantcheva-Poor I, Wickenhauser C, Chemnitz JM, Hun- 348. Dib L, Bitam I, Bensouilah M, Parola P, Raoult D. 2009. First descrip- zelmann N, Krieg T, Hartmann K. 2008. African tick bite fever— tion of Rickettsia monacensis in Ixodes ricinus in Algeria. Clin. Microbiol. papulovesicular exanthem with fever after staying in South Africa. J. Infect. 15(Suppl 2):261–262. Dtsch. Dermatol. Ges. 6:379–381. 349. Khaldi M, Socolovschi C, Benyettou M, Barech G, Biche M, Kernif T, 371. Reshef R, Levo Y, Giladi M. 2007. African tick bite fever in a returned Raoult D, Parola P. 2012. Rickettsiae in arthropods collected from the traveler. Isr. Med. Assoc. J. 9:680–681. North African hedgehog (Atelerix algirus) and the desert hedgehog (Par- 372. Atias D, Meltzer E, Leshem E, Schwartz E. 2010. Rickettsia africae aechinus aethiopicus) in Algeria. Comp. Immunol. Microbiol. Infect. Dis. infection among participants in a women’s safari to South Africa. 35:117–122. Harefuah 149:572–575, 620. (In Hebrew.) 350. Beati L, Patel J, Lucas-Williams H, Adakal H, Kanduma EG, Tembo- 373. Beltrame A, Angheben A, Casolari S, Castelli F, Magnani G, Gaiera G, Mwase E, Krecek R, Mertins JW, Alfred JT, Kelly S, Kelly P. 2012. Brillo F, Cattani G, Anselmi M, Tomasoni L, Prati F, Norberto C, Phylogeography and demographic history of Amblyomma variegatum Socolovschi C, Bisoffi Z, Raoult D, Parola P. 2012. Imported rickett- (Fabricius) (Acari: Ixodidae), the tropical bont tick. Vector Borne Zoo- sioses in Italy. Travel Med. Infect. Dis. 10:201–204. notic Dis. 12:514–525. 374. Fujisawa T, Kadosaka T, Fujita H, Ando S, Takano A, Ogasawara Y, 351. Mediannikov O, Trape JF, Diatta G, Parola P, Fournier PE, Raoult D. Kawabata H, Seishima M. 2012. Rickettsia africae infection in a Japanese 2010. Rickettsia africae, Western Africa. Emerg. Infect. Dis. 16:571–573. traveller with many tick bites. Acta Derm. Venereol. 92:443–444. 352. Socolovschi C, Matsumoto K, Marie JL, Davoust B, Raoult D, Parola 375. Rolain JM, Gouriet F, Brouqui P, Larrey D, Janbon F, Vene S, P. 2007. Identification of rickettsiae, Uganda and Djibouti. Emerg. In- Jarnestrom V, Raoult D. 2005. Concomitant or consecutive infection fect. Dis. 13:1508–1510. with Coxiella burnetii and tickborne diseases. Clin. Infect. Dis. 40:82–88. 353. Mediannikov O, Diatta G, Fenollar F, Sokhna C, Trape JF, Raoult D. 376. Bellini C, Monti M, Potin M, Dalle Ave A, Bille J, Greub G. 2005. 2010. Tick-borne rickettsioses, neglected emerging diseases in rural Sen- Cardiac involvement in a patient with clinical and serological evi- egal. PLoS Negl. Trop. Dis. 4:e821. doi:10.1371/journal.pntd.0000821. dence of African tick-bite fever. BMC Infect. Dis. 5:90. doi:10.1186 354. Ogo NI, de Mera IG, Galindo RC, Okubanjo OO, Inuwa HM, Agbede /1471-2334-5-90. RI, Torina A, Alongi A, Vicente J, Gortazar C, de la Fuente J. 2012. 377. Althaus F, Greub G, Raoult D, Genton B. 2010. African tick-bite fever: Molecular identification of tick-borne pathogens in Nigerian ticks. Vet. a new entity in the differential diagnosis of multiple eschars in travelers. Parasitol. 187:572–577. Description of five cases imported from South Africa to Switzerland. Int. 355. Portillo A, Perez-Martinez L, Santibanez S, Blanco JR, Ibarra V, Oteo J. Infect. Dis. 14(Suppl 3):e274–e276. doi:10.1016/j.ijid.2009.11.021. JA. 2007. Detection of Rickettsia africae in Rhipicephalus (Boophilus) 378. Tsai KH, Lu HY, Tsai JJ, Yu SK, Huang JH, Shu PY. 2008. Human case decoloratus ticks from the Republic of Botswana, South Africa. Am. J. of Rickettsia felis infection, Taiwan. Emerg. Infect. Dis. 14:1970–1972. Trop. Med. Hyg. 77:376–377. 379. Oostvogel PM, van Doornum GJ, Ferreira R, Vink J, Fenollar F, 356. Mediannikov O, Diatta G, Zolia Y, Balde MC, Kohar H, Trape JF, Raoult D. 2007. African tickbite fever in travelers, Swaziland. Emerg. Raoult D. 2012. Tick-borne rickettsiae in Guinea and Liberia. Ticks Tick Infect. Dis. 13:353–355. Borne Dis. 3:43–48. 380. Wieten RW, Hovius JW, Groen EJ, van der Wal AC, de Vries PJ, 357. Mediannikov O, Davoust B, Socolovschi C, Tshilolo L, Raoult D, Beersma MF, Tijsse-Klasen E, Sprong H, Grobusch MP. 2011. Molec- Parola P. 2012. Spotted fever group rickettsiae in ticks and fleas from the ular diagnostics of Rickettsia africae infection in travelers returning from Democratic Republic of the Congo. Ticks Tick Borne Dis. 3:371–373. South Africa to the Netherlands. Vector Borne Zoonotic Dis. 11:1541– 358. Ndip LM, Biswas HH, Nfonsam LE, LeBreton M, Ndip RN, Bissong 1547. MA, Mpoudi-Ngole E, Djoko C, Tamoufe U, Prosser AT, Burke DS, 381. Auce P, Rajakulendran S, Nesbitt A, Chinn R, Kennedy A. 2011. Wolfe ND. 2011. Risk factors for African tick-bite fever in rural central Neurological picture. Internuclear ophthalmoplegia following African Africa. Am. J. Trop. Med. Hyg. 84:608–613. tick bite fever. J. Neurol. Neurosurg. Psychiatry 82:681. doi:10.1136/jnnp 359. Wang JM, Hudson BJ, Watts MR, Karagiannis T, Fisher NJ, Anderson .2010.236216. C, Roffey P. 2009. Diagnosis of Queensland tick typhus and African tick 382. Snape MD, Pollard AJ. 2006. African tick bite fever. Lancet Infect. Dis. bite fever by PCR of lesion swabs. Emerg. Infect. Dis. 15:963–965. 6:750. doi:10.1016/S1473-3099(06)70633-8. 360. Kibsgaard L, Lindberg J, Villumsen S, Larsen CS. 2012. Rickettsiosis is 383. Bottieau E, Clerinx J, Van den Enden E, Van Esbroeck M, Cole- a neglected cause of fever in returned travellers. Ugeskr. Laeger. 174: bunders R, Van Gompel A, Van den Ende J. 2007. Fever after a stay in 1529–1530. (In Danish.) the tropics: diagnostic predictors of the leading tropical conditions. 361. Stephany D, Buffet P, Rolain JM, Raoult D, Consigny PH. 2009. Medicine (Baltimore) 86:18–25. Rickettsia africae infection in man after travel to Ethiopia. Emerg. Infect. 384. Daneman N, Slinger R. 2008. Tache noire. CMAJ 178:841. doi:10.1503 Dis. 15:1867–1869. /cmaj.070102.

October 2013 Volume 26 Number 4 cmr.asm.org 697 Parola et al.

385. Jensenius M, Davis X, von Sonnenburg F, Schwartz E, Keystone JS, Zoller L, Dobler G, Essbauer S. 2012. Rickettsia raoultii, the predomi- Leder K, Lopez-Velez R, Caumes E, Cramer JP, Chen L, Parola P. nant Rickettsia found in Mongolian Dermacentor nuttalli. Ticks Tick 2009. Multicenter GeoSentinel analysis of rickettsial diseases in interna- Borne Dis. 3:227–231. tional travelers, 1996-2008. Emerg. Infect. Dis. 15:1791–1798. 405. Ando S, Kurosawa M, Sakata A, Fujita H, Sakai K, Sekine M, Katsumi 386. Mendelson M, Davis XM, Jensenius M, Keystone JS, von Sonnenburg M, Saitou W, Yano Y, Takada N, Takano A, Kawabata H, Hanaoka N, F, Hale DC, Burchard GD, Field V, Vincent P, Freedman DO. 2010. Watanabe H, Kurane I, Kishimoto T. 2010. Human Rickettsia heilongji- Health risks in travelers to South Africa: the GeoSentinel experience and angensis infection, Japan. Emerg. Infect. Dis. 16:1306–1308. implications for the 2010 FIFA World Cup. Am. J. Trop. Med. Hyg. 406. Mediannikov O, Sidelnikov Y, Ivanov L, Fournier PE, Tarasevich I, 82:991–995. Raoult D. 2006. Far eastern tick-borne rickettsiosis: identification of two 387. Schlagenhauf P, Chen LH, Wilson ME, Freedman DO, Tcheng D, new cases and tick vector. Ann. N. Y. Acad. Sci. 1078:80–88. Schwartz E, Pandey P, Weber R, Nadal D, Berger C, von Sonnenburg 407. Li W, Liu L, Jiang X, Guo X, Garnier M, Raoult D, Parola P. 2009. F, Keystone J, Leder K. 2010. Sex and gender differences in travel- Molecular identification of spotted fever group rickettsiae in ticks col- associated disease. Clin. Infect. Dis. 50:826–832. lected in central China. Clin. Microbiol. Infect. 15(Suppl 2):279–280. 388. Jensenius M, Fournier PE, Fladby T, Hellum KB, Hagen T, Prio T, 408. Zhang LJ, Han J, Xu JG, Turchetto J, Mediannikov O, Rolain JM, Christiansen MS, Vene S, Raoult D, Myrvang B. 2006. Sub-acute Raoult D, Fournier PE. 2009. Identification of a new serotype of Rick- neuropathy in patients with African tick bite fever. Scand. J. Infect. Dis. ettsia heilongjiangensis in wild rats from Guangdong Province, China. 38:114–118. Clin. Microbiol. Infect. 15(Suppl 2):338–339. 389. Schwartz RA, Kapila R, McElligott SC, Atkin SH, Lambert WC. 2012. 409. Liang CW, Zhao JB, Li J, Chang LT, Yu HL, Zhang LX, Zhang LJ, Yu Cutaneous leishmaniasis and rickettsial African tick-bite fever: a combi- XJ. 2012. Spotted fever group Rickettsia in Yunnan Province, China. nation of exotic traveler’s diseases in the same patient. Int. J. Dermatol. Vector Borne Zoonotic Dis. 12:281–286. 51:960–963. 410. Duan C, Meng Y, Wang X, Xiong X, Wen B. 2011. Exploratory study 390. de Almeida DN, Favacho AR, Rozental T, Barcaui H, Guterres A, on pathogenesis of far-eastern spotted fever. Am. J. Trop. Med. Hyg. Gomes R, Levis S, Coelho J, Chebabo A, Costa LC, Andrea S, Barroso 85:504–509. PF, de Lemos ER. 2010. Fatal spotted fever group rickettsiosis due to 411. Gaywee J, Sunyakumthorn P, Rodkvamtook W, Ruang-areerate T, Rickettsia conorii conorii mimicking a hemorrhagic viral fever in a South Mason CJ, Sirisopana N. 2007. Human infection with Rickettsia sp. African traveler in Brazil. Ticks Tick Borne Dis. 1:149–150. related to R. japonica, Thailand. Emerg. Infect. Dis. 13:671–673. 391. Prabhu M, Nicholson WL, Roche AJ, Kersh GJ, Fitzpatrick KA, Oliver 412. Takada N, Fujita H, Kawabata H, Ando S, Sakata A, Takano A, LD, Massung RF, Morrissey AB, Bartlett JA, Onyango JJ, Maro VP, Chaithong U. 2009. Spotted fever group Rickettsia sp. closely related to Kinabo GD, Saganda W, Crump JA. 2011. Q fever, spotted fever group, Rickettsia japonica, Thailand. Emerg. Infect. Dis. 15:610–611. and typhus group rickettsioses among hospitalized febrile patients in 413. Mahara F. 2006. Rickettsioses in Japan and the Far East. Ann. N. Y. Acad. northern Tanzania. Clin. Infect. Dis. 53:e8–e15. doi:10.1093/cid/cir411. Sci. 1078:60–73. 392. Buchau AS, Wurthner JU, Bylaite M, Kukova G, Ruzicka T, Reifen- 414. Tabara K, Kawabata H, Arai S, Itagaki A, Yamauchi T, Katayama T, berger J. 2006. Rickettsiosis subsequent to vacation in Swaziland. Hau- Fujita H, Takada N. 2011. High incidence of rickettsiosis correlated to tarzt 57:328–330. (In German.) prevalence of Rickettsia japonica among Haemaphysalis longicornis tick. J. 393. Yoshikawa H, Kimura M, Ogawa M, Rolain JM, Raoult D. 2005. Vet. Med. Sci. 73:507–510. Laboratory-confirmed Mediterranean spotted fever in a Japanese trav- 415. Sashika M, Abe G, Matsumoto K, Inokuma H. 2010. Molecular survey eler to Kenya. Am. J. Trop. Med. Hyg. 73:1086–1089. of rickettsial agents in feral raccoons (Procyon lotor) in Hokkaido, Japan. 394. Pader V, Nikitorowicz BJ, Abdissa A, Adamu H, Tolosa T, Gashaw A, Jpn. J. Infect. Dis. 63:353–354. Cutler RR, Cutler SJ. 2012. Candidatus Rickettsia hoogstraalii in Ethio- 416. Chung MH, Lee SH, Kim MJ, Lee JH, Kim ES, Kim MK, Park MY, pian Argas persicus ticks. Ticks Tick Borne Dis. 3:338–345. Kang JS. 2006. Japanese spotted fever, South Korea. Emerg. Infect. Dis. 395. Matsumoto K, Parola P, Rolain JM, Jeffery K, Raoult D. 2007. Detec- 12:1122–1124. tion of “Rickettsia sp. strain Uilenbergi” and “Rickettsia sp. strain Davousti” in Amblyomma tholloni ticks from elephants in Africa. BMC 417. Dong X, El Karkouri K, Robert C, Raoult D, Fournier PE. 2012. Microbiol. 7:74. doi:10.1186/1471-2180-7-74. Genomic analysis of Rickettsia japonica strain YHT. J. Bacteriol. 194: 396. Cutler SJ, Browning P, Scott JC. 2006. Ornithodoros moubata, a soft tick 6992. doi:10.1128/JB.01928-12. vector for Rickettsia in east Africa? Ann. N. Y. Acad. Sci. 1078:373–377. 418. Sentausa E, El Karkouri K, Robert C, Raoult D, Fournier PE. 2012. 397. Byambaa B. 2008. Nature-focal rickettsioses in Mongolia. Two decades Genome sequence of “Rickettsia sibirica subsp. mongolitimonae.” J. Bac- of Russian-Mongolian scientific collaboration. Vestn. Ross. Akad. Med. teriol. 194:2389–2390. Nauk 2008(7):44–45. (In Russian.) 419. Harrus S, Perlman-Avrahami A, Mumcuoglu KY, Morick D, Baneth 398. Jang WJ, Choi YJ, Kim JH, Jung KD, Ryu JS, Lee SH, Yoo CK, Paik G. 2011. Molecular detection of Rickettsia massiliae, Rickettsia sibirica HS, Choi MS, Park KH, Kim IS. 2005. Seroepidemiology of spotted mongolitimonae and Rickettsia conorii israelensis in ticks from Israel. Clin. fever group and typhus group rickettsioses in humans, South Korea. Microbiol. Infect. 17:176–180. Microbiol. Immunol. 49:17–24. 420. Chaudhry D, Garg A, Singh I, Tandon C, Saini R. 2009. Rickettsial 399. Mediannikov OI, Makarova VA. 2008. Far-Eastern spotted fever: de- diseases in Haryana: not an uncommon entity. J. Assoc. Physicians India scription of new infectious disease. Vestn. Ross. Akad. Med. Nauk 57:334–337. 2008(7):41–44. (In Russian.) 421. Miah MT, Rahman S, Sarker CN, Khan GK, Barman TK. 2007. Study 400. Tarasevich IV, Mediannikov OY. 2006. Rickettsial diseases in Russia. on 40 cases of rickettsia. Mymensingh Med. J. 16:85–88. Ann. N. Y. Acad. Sci. 1078:48–59. 422. Phongmany S, Rolain JM, Phetsouvanh R, Blacksell SD, Soukkhaseum 401. Shpynov S, Fournier PE, Rudakov N, Arsen’eva I, Granitov M, V, Rasachack B, Phiasakha K, Soukkhaseum S, Frichithavong K, Chu Tarasevich I, Raoult D. 2009. Tick-borne rickettsiosis in the Altay re- V, Keolouangkhot V, Martinez-Aussel B, Chang K, Darasavath C, gion of Russia. Clin. Microbiol. Infect. 15(Suppl 2):313–314. Rattanavong O, Sisouphone S, Mayxay M, Vidamaly S, Parola P, 402. Shpynov SN, Fournier PE, Rudakov NV, Samoilenko IE, Reshetnikova Thammavong C, Heuangvongsy M, Syhavong B, Raoult D, White NJ, TA, Yastrebov VK, Schaiman MS, Tarasevich IV, Raoult D. 2006. Newton PN. 2006. Rickettsial infections and fever, Vientiane, Laos. Molecular identification of a collection of spotted fever group rickettsiae Emerg. Infect. Dis. 12:256–262. obtained from patients and ticks from Russia. Am. J. Trop. Med. Hyg. 423. Stokes PH, Walters BJ. 2009. Spotted fever rickettsiosis infection in a 74:440–443. traveler from Sri Lanka. J. Travel Med. 16:436–438. 403. Cao WC, Zhan L, De Vlas SJ, Wen BH, Yang H, Richardus JH, 424. Joshi HS, Thomas M, Warrier A, Kumar S. 2012. Gangrene in cases of Habbema JD. 2008. Molecular detection of spotted fever group Rickett- spotted fever: a report of three cases. BMJ Case Rep. 2012: sia in Dermacentor silvarum from a forest area of northeastern China. J. bcr2012007295. doi:10.1136/bcr-2012-007295. Med. Entomol. 45:741–744. 425. Sentausa E, El Karkouri K, Robert C, Raoult D, Fournier PE. 2012. 404. Speck S, Derschum H, Damdindorj T, Dashdavaa O, Jiang J, Kaysser Genome sequence of Rickettsia conorii subsp. indica, the agent of Indian P, Jigjav B, Nyamdorj E, Baatar U, Munkhbat E, Choijilsuren O, tick typhus. J. Bacteriol. 194:3288–3289. Gerelchuluun O, Romer A, Richards AL, Kiefer D, Scholz H, Wolfel R, 426. Sentausa E, El Karkouri K, Robert C, Raoult D, Fournier PE. 2012.

698 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

Genome sequence of Rickettsia conorii subsp. israelensis, the agent of 446. Pinn TG, Sowden D. 1998. Queensland tick typhus. Aust. N. Z. J. Med. Israeli spotted fever. J. Bacteriol. 194:5130–5131. 28:824–826. 427. Graves S, Stenos J. 2009. Rickettsioses in Australia. Ann. N. Y. Acad. Sci. 447. Unsworth NB, Stenos J, Faa AG, Graves SR. 2007. Three rickettsioses, 1166:151–155. Darnley Island, Australia. Emerg. Infect. Dis. 13:1105–1107. 428. Jiang J, Sangkasuwan V, Lerdthusnee K, Sukwit S, Chuenchitra T, 448. Birch TF, Muller M. 2009. Severe Queensland tick typhus complicated Rozmajzl PJ, Eamsila C, Jones JW, Richards AL. 2005. Human infec- by diabetes in south-eastern Queensland. Med. J. Aust. 191(5):290–291. tion with Rickettsia honei, Thailand. Emerg. Infect. Dis. 11:1473–1475. 449. McBride WJ, Hanson JP, Miller R, Wenck D. 2007. Severe spotted fever 429. Sangkasuwan V, Chatyingmongkol T, Sukwit S, Eamsila C, Chuenchi- group rickettsiosis, Australia. Emerg. Infect. Dis. 13:1742–1744. tra T, Rodkvamtook W, Jiang J, Richards AL, Lerdthusnee K, Jones 450. Sexton DJ, King G, Dwyer B. 1990. Fatal Queensland tick typhus. J. JW. 2007. Description of the first reported human case of spotted fever Infect. Dis. 162:779–780. group rickettsiosis in urban Bangkok. Am. J. Trop. Med. Hyg. 77:891– 451. Barker SC, Murrell A. 2004. Systematics and evolution of ticks with a list 892. of valid genus and species names. Parasitology 129(Suppl):S15–S36. 430. Murphy H, Renvoise A, Pandey P, Parola P, Raoult D. 2011. Rickettsia 452. Roberts FHS. 1970. Australian ticks, Melbourne. Commonwealth Sci- honei infection in human, Nepal, 2009. Emerg. Infect. Dis. 17:1865– entific and Industrial Research Organization, Clayton South, Victoria, 1867. Australia. 431. Xin D, El Karkouri K, Robert C, Raoult D, Fournier PE. 2012. 453. Stenos J, Graves S, Popov VL, Walker DH. 2003. Aponomma hydro- Genomic comparison of Rickettsia honei strain RBT and other Rickettsia sauri, the reptile-associated tick reservoir of Rickettsia honei on Flinders species. J. Bacteriol. 194:4145. doi:10.1128/JB.00802-12. Island, Australia. Am. J. Trop. Med. Hyg. 69:314–317. 432. Motoi Y, Asano M, Inokuma H, Ando S, Kawabata H, Takano A, 454. Unsworth NB, Stenos J, McGregor AR, Dyer JR, Graves SR. 2005. Not Suzuki M. 2013. Detection of Rickettsia tamurae DNA in ticks and wild only ‘Flinders Island’ spotted fever. Pathology 37:242–245. boar (Sus scrofa leucomystax) skins in Shimane Prefecture, Japan. J. Vet. 455. Lane AM, Shaw MD, McGraw EA, O’Neill SL. 2005. Evidence of a Med. Sci. 75:263–267. spotted fever-like rickettsia and a potential new vector from northeastern 433. Imaoka K, Kaneko S, Tabara K, Kusatake K, Morita E. 2011. The first Australia. J. Med. Entomol. 42:918–921. human case of Rickettsia tamurae infection in Japan. Case Rep. Dermatol. 456. Unsworth NB, Stenos J, Graves SR, Faa AG, Cox GE, Dyer JR, Boutlis 3:68–73. CS, Lane AM, Shaw MD, Robson J, Nissen MD. 2007. Flinders Island 434. Rolain JM, Mathai E, Lepidi H, Somashekar HR, Mathew LG, Prakash spotted fever rickettsioses caused by “marmionii” strain of Rickettsia JA, Raoult D. 2006. “Candidatus Rickettsia kellyi,” India. Emerg. Infect. honei, Eastern Australia. Emerg. Infect. Dis. 13:566–573. Dis. 12:483–485. 457. Unsworth N, Graves S, Nguyen C, Kemp G, Graham J, Stenos J. 2008. 435. Keysary A, Eremeeva ME, Leitner M, Din AB, Wikswo ME, Mumcu- Markers of exposure to spotted fever rickettsiae in patients with chronic oglu KY, Inbar M, Wallach AD, Shanas U, King R, Waner T. 2011. illness, including fatigue, in two Australian populations. QJM 101:269– Spotted fever group rickettsiae in ticks collected from wild animals in 274. Israel. Am. J. Trop. Med. Hyg. 85:919–923. 458. Kelly PJ, Beati L, Mason PR, Matthewman LA, Roux V, Raoult D. 1996. Rickettsia africae sp. nov., the etiological agent of African tick bite 436. Tian ZC, Liu GY, Shen H, Xie JR, Luo J, Tian MY. 2012. First report fever. Int. J. Syst. Bacteriol. 46:611–614. on the occurrence of Rickettsia slovaca and Rickettsia raoultii in Der- 459. Eldin C, Mediannikov O, Davoust B, Cabre O, Barre N, Raoult D, macentor silvarum in China. Parasit. Vectors 5:19. doi:10.1186/1756 Parola P. 2011. Emergence of Rickettsia africae, Oceania. Emerg. Infect. -3305-5-19. Dis. 17:100–102. 437. Ahantarig A, Malaisri P, Hirunkanokpun S, Sumrandee C, Trinacha- 460. Owen H, Unsworth N, Stenos J, Robertson I, Clark P, Fenwick S. 2006. rtvanit W, Baimai V. 2011. Detection of Rickettsia and a novel Haema- Detection and identification of a novel spotted fever group rickettsia in physalis shimoga symbiont bacterium in ticks in Thailand. Curr. Micro- Western Australia. Ann. N. Y. Acad. Sci. 1078:197–199. biol. 62:1496–1502. 461. Owen H, Clark P, Stenos J, Robertson I, Fenwick S. 2006. Potentially 438. Inokuma H, Ohashi M, Jilintai, Tanabe S, Miyahara K. 2007. Preva- pathogenic spotted fever group rickettsiae present in Western Australia. lence of tick-borne Rickettsia and Ehrlichia in Ixodes persulcatus and Ix- Aust. J. Rural Health 14:284–285. odes ovatus in Tokachi district, Eastern Hokkaido, Japan. J. Vet. Med. Sci. 462. Li AY, Adams PJ, Abdad MY, Fenwick SG. 2010. High prevalence of 69:661–664. Rickettsia gravesii sp. nov. in Amblyomma triguttatum collected from fe- 439. Filippova NA. 1997. Ixodid ticks from subfamily Ambliomminae, p 436. ral pigs. Vet. Microbiol. 146:59–62. In Tsalolikhin SY (ed), Fauna of Russia and neighboring countries. 463. Pearce RL, Grove DI. 1987. in soldiers who were biv- Arachnidae. Nauka, St Petersburg, Russia. ouacked in the Perth region. Med. J. Aust. 146:238–240. 440. Jilintai, Seino N, Matsumoto K, Hayakawa D, Suzuki M, Hata H, 464. Izzard L, Graves S, Cox E, Fenwick S, Unsworth N, Stenos J. 2009. Kondo S, Yokoyama N, Inokuma H. 2008. Serological and molecular Novel rickettsia in ticks, Tasmania, Australia. Emerg. Infect. Dis. 15: survey of rickettsial infection in cattle and sika deer in a pastureland in 1654–1656. Hidaka District, Hokkaido, Japan. Jpn. J. Infect. Dis. 61:315–317. 465. Vilcins IM, Old JM, Deane EM. 2008. Detection of a spotted fever group 441. Tsui PY, Tsai KH, Weng MH, Hung YW, Liu YT, Hu KY, Lien JC, Lin Rickettsia in the tick Ixodes tasmani collected from koalas in Port Mac- PR, Shaio MF, Wang HC, Ji DD. 2007. Molecular detection and char- quarie, Australia. J. Med. Entomol. 45:745–750. acterization of spotted fever group rickettsiae in Taiwan. Am. J. Trop. 466. Angelakis E, Richet H, Rolain JM, La Scola B, Raoult D. 2012. Med. Hyg. 77:883–890. Comparison of real-time quantitative PCR and culture for the diagnosis 442. Tsai KH, Wang HC, Chen CH, Huang JH, Lu HY, Su CL, Shu PY. of emerging rickettsioses. PLoS Negl. Trop. Dis. 6:e1540. doi:10.1371 2008. Isolation and identification of a novel spotted fever group rickett- /journal.pntd.0001540. sia, strain IG-1, from Ixodes granulatus ticks collected on Orchid Island 467. Stenos J, Graves SR, Unsworth NB. 2005. A highly sensitive and specific (Lanyu), Taiwan. Am. J. Trop. Med. Hyg. 79:256–261. real-time PCR assay for the detection of spotted fever and typhus group 443. Fujita H, Kadosaka T, Nitta Y, Ando S, Takano A, Watanabe H, rickettsiae. Am. J. Trop. Med. Hyg. 73:1083–1085. Kawabata H. 2008. Rickettsia sp. in Ixodes granulatus ticks, Japan. Emerg. 468. Kidd L, Maggi R, Diniz PP, Hegarty B, Tucker M, Breitschwerdt E. Infect. Dis. 14:1963–1965. 2008. Evaluation of conventional and real-time PCR assays for detection 444. Kawabata H, Ando S, Kishimoto T, Kurane I, Takano A, Nogami S, and differentiation of spotted fever group Rickettsia in dog blood. Vet. Fujita H, Tsurumi M, Nakamura N, Sato F, Takahashi M, Ushijima Y, Microbiol. 129:294–303. Fukunaga M, Watanabe H. 2006. First detection of Rickettsia in soft- 469. Renvoise A, Rolain JM, Socolovschi C, Raoult D. 2012. Widespread use bodied ticks associated with seabirds, Japan. Microbiol. Immunol. 50: of real-time PCR for rickettsial diagnosis. FEMS Immunol. Med. Micro- 403–406. biol. 64:126–129. 445. Chahan B, Jian Z, Jilintai, Miyahara K, Tanabe S, Xuan X, Sato Y, 470. Fournier PE, Drancourt M, Raoult D. 2007. Bacterial genome sequenc- Moritomo T, Nogami S, Mikami T, Maruyama S, Inokuma H. 2007. ing and its use in infectious diseases. Lancet Infect. Dis. 7:711–723. Detection of DNA closely related to ‘Candidatus Rickettsia principis’ in 471. Mouffok N, Socolovschi C, Benabdellah A, Renvoise A, Parola P, Haemaphysalis danieli recovered from cattle in Xinjiang Uygur Autono- Raoult D. 2011. Diagnosis of rickettsioses from eschar swab samples, mous Region Area, China. Vet. Parasitol. 144:184–187. Algeria. Emerg. Infect. Dis. 17:1968–1969.

October 2013 Volume 26 Number 4 cmr.asm.org 699 Parola et al.

472. Socolovschi C, Renvoise A, Brouqui P, Parola P, Raoult D. 2012. The time of flight mass spectrometry for rapid identification of tick vectors. J. use of eschar swabs for the diagnosis of African tick-bite fever. Ticks Tick Clin. Microbiol. 51:522–528. Borne Dis. 3:361–363. 478. Botelho-Nevers E, Socolovschi C, Raoult D, Parola P. 2012. Treatment 473. Myers T, Lalani T, Dent M, Jiang J, Daly PL, Maguire JD, Richards AL. of Rickettsia spp. infections: a review. Expert Rev. Anti Infect. Ther. 10: 2013. Detecting Rickettsia parkeri infection from eschar swab specimens. 1425–1437. Emerg. Infect. Dis. 19:778–780. 479. Audoly G, Vincentelli R, Edouard S, Georgiades K, Mediannikov O, 474. Parola P, Raoult D. 2001. Ticks and tickborne bacterial diseases in Gimenez G, Socolovschi C, Mege JL, Cambillau C, Raoult D. 2011. humans: an emerging infectious threat. Clin. Infect. Dis. 32:897–928. Effect of rickettsial toxin VapC on its eukaryotic host. PLoS One 475. Seng P, Rolain JM, Fournier PE, La Scola B, Drancourt M, Raoult D. 6:e26528. doi:10.1371/journal.pone.0026528. 2010. MALDI-TOF-mass spectrometry applications in clinical microbi- 480. Botelho-Nevers E, Edouard S, Leroy Q, Raoult D. 2012. Deleterious ology. Future Microbiol. 5:1733–1754. effect of ciprofloxacin on Rickettsia conorii-infected cells is linked to 476. Karger A, Kampen H, Bettin B, Dautel H, Ziller M, Hoffmann B, Suss toxin-antitoxin module up-regulation. J. Antimicrob. Chemother. 67: J, Klaus C. 2012. Species determination and characterization of devel- 1677–1682. opmental stages of ticks by whole-animal matrix-assisted laser desorp- 481. Jensenius M, Parola P, Raoult D. 2006. Threats to international trav- tion/ionization mass spectrometry. Ticks Tick Borne Dis. 3:78–89. ellers posed by tick-borne diseases. Travel. Med. Infect. Dis. 4:4–13. 477. Yssouf A, Flaudrops C, Drali R, Kernif T, Socolovschi C, Berenger JM, 482. Holland CA, Kiechle FL. 2005. Point-of-care molecular diagnostic sys- Raoult D, Parola P. 2013. Matrix-assisted laser desorption ionization- tems—past, present and future. Curr. Opin. Microbiol. 8:504–509.

Philippe Parola, M.D., Ph.D., is a French clini- Cristina Socolovschi is an infectious diseases cian and Professor of Infectious Diseases and clinician who obtained her M.D. degree at the Tropical Medicine (IDTM) at the Faculty of faculty of Chisinau, Moldova. In 2002, she Medicine of Marseille, Aix-Marseille Univer- joined the University Hospital of Marseille and sity, France. There, he is director in charge of started her research activity at the Unité des the IDTM Residency program. His clinical Rickettsies. Working on the relationship be- medical activities take place in the University tween spotted fever group rickettsiae and ixodid Hospital Institute for IDTM of Marseille, where ticks, she obtained her Ph.D. degree in 2009. he is particularly involved in management of ill She is now in charge of diagnosis and manage- returned travelers. His research interests in- ment of vector-borne diseases, especially rick- clude vector-borne rickettsioses and emerging ettsiosis, in the infectious diseases department infectious diseases. By January 2013, Dr. Parola had coauthored more than of the University Hospital of Marseille and continues her research activity 270 publications in the international literature. He is Director of the WHO with the team of Philippe Parola. Her research interests include tropical Collaborative Center for Rickettsial and Other Arthropod Borne Bacterial diseases and medical entomology, focused on relationships of hosts and Diseases and a worldwide-recognized expert on tick-borne rickettsioses. In pathogens in rickettsial diseases. She has published more than 50 research the field of travel medicine, he is Director of EuroTravNet, the European articles in the field of vector-borne diseases. CDC Collaborative Network for Travel and Tropical Medicine; and he has been appointed as GeoSentinel, Global Surveillance Network, Project Director—Europe. Marcelo B. Labruna is a veterinarian with a Ph.D. in epidemiology and a member of the So- ciedade de Investigadores de Antricola (SIA). Christopher D. Paddock is a rickettsiologist He is an Associate Professor of Animal Parasitic and pathologist at the Centers for Disease Con- Diseases of the Faculty of Veterinary Medicine trol and Prevention (CDC) in Atlanta, GA. Dr. of the University of São Paulo, Brazil. His re- Paddock received his B.S. and M.S. degrees in search interest has been systematic biology and Entomology at the University of California, Da- ecology of neotropical ticks and tick-borne dis- vis, in 1981 and 1986, respectively, and his M.D. eases, with emphasis on rickettsioses. He is the and M.P.H.T.M. degrees at Tulane University curator of the Coleção Nacional de Carrapatos in New Orleans, LA, in 1990. He completed his (CNC), one of the largest tick collections of residency in Anatomic Pathology and Labora- Latin America. In the past years, he has provided major contributions in the tory Medicine at the University of California, field of vector-associated rickettsiae. San Francisco, in 1995. His employment with the CDC began in 1996, as medical officer in the Viral and Rickettsial Zoo- noses Branch, where he worked until taking a position as staff pathologist with the Infectious Disease Pathology Branch in 2003. He has authored or coauthored approximately 150 scientific publications and 20 book chapters. His research interests include clinical, diagnostic, and epidemiologic aspects of rickettsial diseases, primarily newly recognized spotted fever group rickettsioses.

700 cmr.asm.org Clinical Microbiology Reviews Tick-Borne Rickettsioses around the World

Oleg Mediannikov graduated from medical John Stenos completed a science degree with university in Khabarovsk, Russia, in 1998 and majors in microbiology and biochemistry at the specialized in infectious diseases. With a re- University of Melbourne in Australia in 1989. search interest focusing on vector-borne dis- This was followed immediately with an Honors eases, including anaplasmosis, spotted fever, project assessing various assays in quantifying and borrelioses, he obtained his Ph.D. degree in Rickettsia australis. He continued in the same 2004. Particularly, he identified the role of Rick- field with a Ph.D. project looking at the charac- ettsia heilongjiangensis as a cause of tick-borne terization of Australian rickettsial agents. His spotted fever in the Russian Far East. He then love of rickettsiology was cemented further with joined Didier Raoult’s team in France, and since a postdoctoral fellow position in the United 2011, he has led a research group within the IRD States. His research in rickettsial genomics was component in Senegal. There, he continues his studies of the origins of acute undertaken in the world-renowned rickettsial laboratory, with direction febrile diseases in Africa, particularly emerging vector-borne diseases (re- from Dr. David Walker, at the University of Texas Medical Branch, USA. He lapsing fever, spotted fevers, and bartonelloses). He is an expert on the iso- was then invited back to Australia by a pioneer in Australian rickettsiologist, lation of fastidious bacteria. He isolated and described such bacteria, includ- Dr. Stephen Graves, to help run the Australian Rickettsial Reference Labo- ing new species such as Rickettsia raoultii, Diplorickettsia massiliensis, ratory in 1998. In the following years, the laboratory established a world- Orientia massiliensis, Bartonella senegalensis, Bartonella florenciae, and Bar- renowned reputation in its diagnostics and research activities supporting tonella massiliensis. both scientists and students in this emerging field.

Tahar Kernif has obtained the title of veterinary Idir Bitam is Associate Professor at the Univer- doctor and parasitologist at the Veterinary sity of Boumerdes, Algeria. After having ob- School of Algiers, Algeria. Subsequently, he ob- tained a master’s degree in Entomology in Al- tained his Ph.D. degree at the Faculty of Medi- giers, Algeria, he completed a Ph.D. degree at cine of Marseille, Aix-Marseille University, the Faculty of Medicine of Marseille, Aix-Mar- France. He is now a research fellow on vector seille University, France, under the direction of diseases and arthropods at the Pasteur Institute Didier Raoult. He published most of the current of Algiers, Algeria. He is also working within the available data about tick- and flea-associated MABAVECT team created by Idir Bitam. His rickettsiae from Algeria. Back in Algeria, he has research interests focus on vector-borne infec- created the Young Investigators research team tious diseases and medical entomology because “Malbavect,” in partnership with the IRD. His these diseases are underestimated and misdiagnosed in North Africa. research interests include vector-borne bacterial diseases, particularly flea- and tick-borne diseases.

Mohammad Yazid Abdad received his Ph.D. from Murdoch University, Western Australia, Pierre-Edouard Fournier, M.D., Ph.D., is a investigating the epidemiology and prevalence clinical microbiologist and Professor of Micro- of a novel rickettsia in humans, feral pigs, and biology at the Faculty of Medicine of Marseille, potential invertebrate reservoirs. He then pro- Aix-Marseille University, France. There, within ceeded to complete a 3-year postdoctoral fel- the Research Unit in Infectious and Tropical lowship with the Australian Rickettsial Refer- Emergent Diseases, he is Director of the French ence Laboratory in Geelong, Australia, studying reference center for the diagnosis of rickettsio- rickettsial organisms in Australia and the re- ses, bartonelloses, and Q fever. He specializes in gion. He is currently employed by the Papua the diagnosis of infectious diseases, notably in- New Guinea Institute of Medical Research, fections caused by intracellular bacteria. Dr. Goroka, Papua New Guinea, as a Senior Research Fellow. His current re- Fournier authored or coauthored more than search focus encompasses zoonotic and emerging diseases, and he spends 250 internationally published articles. much of his time in the jungles and rural parts of Papua New Guinea. He Continued next page leads a team of scientists investigating zoonotic transmission, emerging dis- ease outbreaks, and prevalences of various neglected diseases in local com- munities and animal populations (both wild and domestic).

October 2013 Volume 26 Number 4 cmr.asm.org 701 Parola et al.

Didier Raoult holds M.D. and Ph.D. degrees, specializes in infectious diseases, and is Profes- sor of Microbiology at the Faculty of Medicine of Marseille, Aix-Marseille University. There, in 1984, he created, ex nihilo, his research labora- tory, the Rickettsia Unit. It has now become the Research Unit in Infectious and Tropical Emer- gent Diseases, collaborating with the CNRS (National Center for the Scientific Research), IRD (Research for the Development Institute), and INSERM (National Institute of Health and Medical Research). Since 2011, he has been the director of the University Hospital Institute Mediterranée Infection, a 600-person medical institute working on infectious diseases. It includes the largest diagnostic and research microbiology laboratory in France. Providing one of the largest genomic, transcriptomic, and proteomic platforms, it is a leader within the fields of microbiology, infectious diseases, and emerging infections. As of 2013, Dr. Raoult has published around 1,700 indexed publications and remains the world expert in the field of rickettsioses.

702 cmr.asm.org Clinical Microbiology Reviews